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Mitochondria-Translocated PGK1 Functions as a Protein Kinase to Coordinate Glycolysis and the TCA Cycle in Tumorigenesis.
- Source :
-
Molecular cell [Mol Cell] 2016 Mar 03; Vol. 61 (5), pp. 705-719. - Publication Year :
- 2016
-
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.<br /> (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cell Hypoxia
Cell Line, Tumor
Cell Proliferation
Enzyme Activation
ErbB Receptors genetics
ErbB Receptors metabolism
Extracellular Signal-Regulated MAP Kinases metabolism
Female
Glioblastoma genetics
Glioblastoma pathology
Humans
Mice, Nude
Mitochondria pathology
Mutation
NIMA-Interacting Peptidylprolyl Isomerase
Peptidylprolyl Isomerase genetics
Peptidylprolyl Isomerase metabolism
Phosphoglycerate Kinase genetics
Phosphorylation
Prognosis
Protein Binding
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases metabolism
Protein Transport
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
Citric Acid Cycle
Glioblastoma enzymology
Glycolysis
Mitochondria enzymology
Phosphoglycerate Kinase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 61
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 26942675
- Full Text :
- https://doi.org/10.1016/j.molcel.2016.02.009