title: Mitochondria-Translocated PGK1 Functions as a Protein Kinase to Coordinate Glycolysis and the TCA Cycle in Tumorigenesis.
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.
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Li
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Institute of Cell Metabolism and Disease, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Meisenhelder
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Hawke
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Institute of Cell Metabolism and Disease, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.affiliation: Laboratory of Thoracic Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 10002, China.
authors.forename: Jie
authors.initials: J
authors.lastname: He
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Hunter
authors.affiliation: The Institute of Cell Metabolism and Disease, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA. Electronic address: zhiminlu@mdanderson.org.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002952:Citric Acid Cycle; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006019:Glycolysis; D006801:Humans; D008819:Mice, Nude; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism; D010735:Phosphoglycerate Kinase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: C117307:KRAS protein, human; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; C577282:PGK1 protein, human; D010735:Phosphoglycerate Kinase; D016283:Proto-Oncogene Proteins p21(ras); C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse
keywords: B-Raf; EGFR; K-Ras; PDH; PDHK1; PGK1; glycolysis; hypoxia; mitochondria; phosphorylation; tumorigenesis