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ERK2 Phosphorylates PFAS to Mediate Posttranslational Control of De Novo Purine Synthesis
Eunus S Ali1, Umakant Sahu1, Elodie Villa1
1Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
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.
Insights
The RAS-ERK pathway rapidly boosts purine synthesis by phosphorylating the PFAS enzyme, supplying building blocks essential for cell growth and proliferation. This finding reveals a direct link between signaling and metabolism in cancer.
Area of Science:
- Molecular Biology
- Cellular Metabolism
- Cancer Signaling
Background:
- The RAS-ERK/MAPK pathway regulates cell growth and proliferation by influencing gene expression.
- Direct, rapid metabolic regulation by the RAS-ERK pathway is not well understood.
- Metabolic alterations are crucial for cancer cell growth and proliferation.
Purpose of the Study:
- To investigate the direct and rapid regulation of metabolic pathways by the RAS-ERK/MAPK pathway.
- To identify specific molecular mechanisms linking ERK signaling to metabolic flux.
- To determine the role of purine synthesis in RAS-ERK-driven cell proliferation.
Main Methods:
- Activation of ERK signaling (physiological and oncogenic) in cellular models.
- Metabolic flux analysis of the de novo purine synthesis pathway.
- Site-directed mutagenesis of the PFAS enzyme (T619A).
- Assessment of cell proliferation, colony formation, and tumor growth.
Main Results:
- ERK signaling activation acutely stimulates de novo purine synthesis.
- ERK2 phosphorylates phosphoribosylformylglycinamidine synthase (PFAS) at Threonine 619 (T619).
- Nonphosphorylatable PFAS (T619A) impairs purine synthesis, cancer cell proliferation, and tumor growth.
Conclusions:
- ERK2-mediated phosphorylation of PFAS is a key mechanism linking RAS-ERK signaling to increased nucleic acid synthesis.
- This metabolic adaptation supports the anabolic demands of cell growth and proliferation.
- Targeting ERK-PFAS interaction may offer therapeutic strategies for RAS-driven cancers.
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