ERK2 Phosphorylates PFAS to Mediate Posttranslational Control of De Novo Purine Synthesis

Mol Cell. 2020 Jun 18;78(6):1178-1191.e6. doi: 10.1016/j.molcel.2020.05.001. Epub 2020 Jun 1.

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.

Keywords: ERK; FGAM; MAPK; PFAS; RAS; cancer; nucleotide synthesis; posttranslational modification; purine metabolism; tumor growth.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor / genetics
  • Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor / metabolism*
  • Cell Cycle / physiology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • HeLa Cells
  • Humans
  • MAP Kinase Signaling System / physiology
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Phosphorylation
  • Purines / biosynthesis*
  • Purines / metabolism
  • Signal Transduction / physiology
  • ras Proteins / metabolism

Substances

  • Purines
  • Extracellular Signal-Regulated MAP Kinases
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • ras Proteins
  • Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor
  • phosphoribosylformylglycinamidine synthetase