My previous studies revealed new connections between mTORC1 signaling and cellular metabolism. The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved protein kinase that, as the core component of mTOR complex 1 (mTORC1), senses cellular growth conditions (i.e. nutrients, energy, growth factors, stress) to properly control cell growth and proliferation.
Indeed, we showed that mTORC1 activation in response to physiological or genetic stimuli led to the acute induction of metabolic flux through the de novo pyrimidine synthesis pathway, which provides the nucleotide building blocks of RNA and DNA required for anabolic cell growth and proliferation. mTORC1 signaling post-translationally regulates this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates Ser1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. This study demonstrates that mTORC1 serves as a molecular link between growth signals and acute control over nucleotide synthesis. The direct regulation of CAD by S6K1 serves as a mechanism to increase the pool of nucleotides available for the nucleic acid synthesis required for cell growth and proliferation.
In addition to the control of pyrimidine synthesis by mTORC1, we have demonstrated that mTORC1 signaling controls flux over purine synthesis through transcriptional effects on multiple enzymes within the pathway, as well as the pentose phosphate, the de novo serine synthesis, and mitochondrial tetrahydrofolate (mTHF) pathways. The enzyme MTHFD2 (Methylene Tetrahydrofolate Dehydrogenase 2) is particularly sensitive to mTORC1 signaling across settings and, as part of the mTHF cycle, provides cytosolic one-carbon units required for purine synthesis. mTORC1 induces MTHFD2 expression and purine synthesis through downstream activation of the ATF4 transcription factor. Thus, mTORC1 signaling stimulates the mTHF cycle, which contributes to the enhanced production of purine nucleotides.
Uncovering the role of signaling pathways in the regulation of cellular metabolism
Using isotopic tracing experiments, proteomics and genetic approaches, my lab investigates whether additional signaling pathways could regulate metabolic pathways that supply small metabolites to sustain nucleotide synthesis independently of mTORC1 signaling. In addition to nucleotide metabolism, we also study molecular connections between signaling pathway and global cancer cell metabolism. Molecular points of regulations of metabolic pathways mediated by oncogenic signals could give selective advantages to cancer cells to grow and proliferate. The initial discovery that cancer cells exhibit atypical metabolic characteristics can be traced to the pioneering work of Otto Warburg, over the first half of the twentieth century.
Deciphering the interplay between oncogenic processes and metabolic pathways that contribute to metabolic reprogramming in a given setting may serve as a critical factor in determining therapeutic targets that yield greatest drug efficacy with marginal harmful effect on normal cells. Our research will enable further progress in the exploitation of unusual metabolic features in cancer as a means of therapeutic intervention.