Abstract
The RAS-ERK/MAPK (RAS-extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway integrates growth-promoting signals to stimulate cell growth and proliferation, at least in part, through alterations in metabolic gene expression. However, examples of direct and rapid regulation of the metabolic pathways by the RAS-ERK pathway remain elusive. We find that physiological and oncogenic ERK signaling activation leads to acute metabolic flux stimulation through the de novo purine synthesis pathway, thereby increasing building block availability for RNA and DNA synthesis, which is required for cell growth and proliferation. We demonstrate that ERK2, but not ERK1, phosphorylates the purine synthesis enzyme PFAS (phosphoribosylformylglycinamidine synthase) at T619 in cells to stimulate de novo purine synthesis. The expression of nonphosphorylatable PFAS (T619A) decreases purine synthesis, RAS-dependent cancer cell-colony formation, and tumor growth. Thus, ERK2-mediated PFAS phosphorylation facilitates the increase in nucleic acid synthesis required for anabolic cell growth and proliferation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1178-1191.e6 |
| Journal | Molecular cell |
| Volume | 78 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 18 2020 |
Funding
The authors thank B.D. Manning and G. Hoxhaj for helpful discussion and comments and Z. Djabari and M. Yuan for technical assistance. This work was supported by the Lynn Sage (to I.B.-S.) and LAM Foundations (grant LAM0127C01-18 to I.B.-S.), and by the National Institutes of Health (NIH) (grants R00CA194192 and R01GM135587 to I.B.-S. and grants 5P01CA120964 and 5P30CA006516 to J.M.A.). The authors thank B.D. Manning and G. Hoxhaj for helpful discussion and comments and Z. Djabari and M. Yuan for technical assistance. This work was supported by the Lynn Sage (to I.B.-S.) and LAM Foundations (grant LAM0127C01-18 to I.B.-S.), and by the National Institutes of Health (NIH) (grants R00CA194192 and R01GM135587 to I.B.-S. and grants 5P01CA120964 and 5P30CA006516 to J.M.A.). E.S.A. and U.S. performed and analyzed all experiments and prepared the manuscript. E.V. performed the qPCR experiments. B.P.O. provided assistance to E.S.A. U.S. and E.V. P.G. and J.M.A. performed the LC-MS/MS experiments. C.B. and A.W.W. produced the phospho-specific PFAS antibody. I.B.-S. supervised the project, reviewed all experimental data, and prepared the manuscript. All the authors have reviewed, commented on, and edited the manuscript. The authors declare no competing interests.
Keywords
- ERK
- FGAM
- MAPK
- PFAS
- RAS
- cancer
- nucleotide synthesis
- posttranslational modification
- purine metabolism
- tumor growth
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
