Journal
MOLECULAR CELL
Volume 61, Issue 5, Pages 705-719Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.02.009
Keywords
-
Categories
Funding
- National Cancer Institute [2R01 CA109035, 1R0 CA169603, 2P50CA127001]
- National Institute of Neurological Disorders and Stroke [1R01NS089754, CA16672, CA82683]
- Sister Institution Network Fund from The University of Texas MD Anderson Cancer Center
- Odyssey Fellowship from The University of Texas MD Anderson Cancer Center
- National Science Foundation of China [81572700]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available