Mitochondria-Translocated PGK1 Functions as a Protein Kinase to Coordinate Glycolysis and the TCA Cycle in Tumorigenesis

Mol Cell. 2016 Mar 3;61(5):705-719. doi: 10.1016/j.molcel.2016.02.009.

Abstract

It is unclear how the Warburg effect that exemplifies enhanced glycolysis in the cytosol is coordinated with suppressed mitochondrial pyruvate metabolism. We demonstrate here that hypoxia, EGFR activation, and expression of K-Ras G12V and B-Raf V600E induce mitochondrial translocation of phosphoglycerate kinase 1 (PGK1); this is mediated by ERK-dependent PGK1 S203 phosphorylation and subsequent PIN1-mediated cis-trans isomerization. Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex. This reduces mitochondrial pyruvate utilization, suppresses reactive oxygen species production, increases lactate production, and promotes brain tumorigenesis. Furthermore, PGK1 S203 and PDHK1 T338 phosphorylation levels correlate with PDH S293 inactivating phosphorylation levels and poor prognosis in glioblastoma patients. This work highlights that PGK1 acts as a protein kinase in coordinating glycolysis and the tricarboxylic acid (TCA) cycle, which is instrumental in cancer metabolism and tumorigenesis.

Keywords: B-Raf; EGFR; K-Ras; PDH; PDHK1; PGK1; glycolysis; hypoxia; mitochondria; phosphorylation; tumorigenesis.

Publication types

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

MeSH terms

  • Animals
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Proliferation
  • Citric Acid Cycle*
  • Enzyme Activation
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Glioblastoma / enzymology*
  • Glioblastoma / genetics
  • Glioblastoma / pathology
  • Glycolysis*
  • Humans
  • Mice, Nude
  • Mitochondria / enzymology*
  • Mitochondria / pathology
  • Mutation
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / metabolism
  • Phosphoglycerate Kinase / genetics
  • Phosphoglycerate Kinase / metabolism*
  • Phosphorylation
  • Prognosis
  • Protein Binding
  • Protein Transport
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Pyruvate Dehydrogenase Complex / genetics
  • Pyruvate Dehydrogenase Complex / metabolism
  • RNA Interference
  • Rats
  • Signal Transduction
  • Time Factors
  • Transfection

Substances

  • KRAS protein, human
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Pyruvate Dehydrogenase Complex
  • EGFR protein, human
  • ErbB Receptors
  • BRAF protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins B-raf
  • Extracellular Signal-Regulated MAP Kinases
  • PGK1 protein, human
  • Phosphoglycerate Kinase
  • Proto-Oncogene Proteins p21(ras)
  • PIN1 protein, human
  • Peptidylprolyl Isomerase
  • Pin1 protein, mouse