Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation

Nat Commun. 2013;4:1790. doi: 10.1038/ncomms2759.

Abstract

How oncogenic signalling coordinates glycolysis and anabolic biosynthesis in cancer cells remains unclear. We recently reported that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) regulates anabolic biosynthesis by controlling intracellular levels of its substrate 3-phosphoglycerate and product 2-phosphoglycerate. Here we report a novel mechanism in which Y26 phosphorylation enhances PGAM1 activation through release of inhibitory E19 that blocks the active site, stabilising cofactor 2,3-bisphosphoglycerate binding and H11 phosphorylation. We also report the crystal structure of H11-phosphorylated PGAM1 and find that phospho-H11 activates PGAM1 at least in part by promoting substrate 3-phosphoglycerate binding. Moreover, Y26 phosphorylation of PGAM1 is common in human cancer cells and contributes to regulation of 3-phosphoglycerate and 2-phosphoglycerate levels, promoting cancer cell proliferation and tumour growth. As PGAM1 is a negative transcriptional target of TP53, and is therefore commonly upregulated in human cancers, these findings suggest that Y26 phosphorylation represents an additional acute mechanism underlying phosphoglycerate mutase 1 upregulation.

Publication types

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

MeSH terms

  • 2,3-Diphosphoglycerate / metabolism
  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Enzyme Stability
  • Glyceric Acids / metabolism
  • Glycolysis
  • Histidine / metabolism
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Neoplasms / enzymology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Phosphoglycerate Mutase / chemistry*
  • Phosphoglycerate Mutase / metabolism*
  • Phosphorylation
  • Phosphotyrosine / metabolism*

Substances

  • Glyceric Acids
  • 2,3-Diphosphoglycerate
  • Phosphotyrosine
  • 2-phosphoglycerate
  • Histidine
  • 3-phosphoglycerate
  • Phosphoglycerate Mutase

Associated data

  • PDB/4GPI
  • PDB/4GPZ