title: Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism.
abstract: Many tumor cells rely on aerobic glycolysis instead of oxidative phosphorylation for their continued proliferation and survival. Myc and HIF-1 are believed to promote such a metabolic switch by, in part, upregulating gene expression of pyruvate dehydrogenase (PDH) kinase 1 (PDHK1), which phosphorylates and inactivates mitochondrial PDH and consequently pyruvate dehydrogenase complex (PDC). Here we report that tyrosine phosphorylation enhances PDHK1 kinase activity by promoting ATP and PDC binding. Functional PDC can form in mitochondria outside of the matrix in some cancer cells and PDHK1 is commonly tyrosine phosphorylated in human cancers by diverse oncogenic tyrosine kinases localized to different mitochondrial compartments. Expression of phosphorylation-deficient, catalytic hypomorph PDHK1 mutants in cancer cells leads to decreased cell proliferation under hypoxia and increased oxidative phosphorylation with enhanced mitochondrial utilization of pyruvate and reduced tumor growth in xenograft nude mice. Together, tyrosine phosphorylation activates PDHK1 to promote the Warburg effect and tumor growth.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Taro
authors.initials: T
authors.lastname: Hitosugi
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chung
authors.forename: Katherine
authors.initials: K
authors.lastname: Lythgoe
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Jianxin
authors.initials: J
authors.lastname: Xie
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Ge
authors.forename: Ting-Lei
authors.initials: TL
authors.lastname: Gu
authors.forename: Roberto D
authors.initials: RD
authors.lastname: Polakiewicz
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Roesel
authors.forename: Georgia Z
authors.initials: GZ
authors.lastname: Chen
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Sumin
authors.initials: S
authors.lastname: Kang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D005260:Female; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014183:Transplantation, Heterologous; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014443:Tyrosine; D017346:Protein Serine-Threonine Kinases