title: Tyr-94 phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth.
abstract: Many cancer cells rely more on aerobic glycolysis (the Warburg effect) than mitochondrial oxidative phosphorylation and catabolize glucose at a high rate. Such a metabolic switch is suggested to be due in part to functional attenuation of mitochondria in cancer cells. However, how oncogenic signals attenuate mitochondrial function and promote the switch to glycolysis remains unclear. We previously reported that tyrosine phosphorylation activates and inhibits mitochondrial pyruvate dehydrogenase kinase (PDK) and phosphatase (PDP), respectively, leading to enhanced inhibitory serine phosphorylation of pyruvate dehydrogenase (PDH) and consequently inhibition of pyruvate dehydrogenase complex (PDC) in cancer cells. In particular, Tyr-381 phosphorylation of PDP1 dissociates deacetylase SIRT3 and recruits acetyltransferase ACAT1 to PDC, resulting in increased inhibitory lysine acetylation of PDHA1 and PDP1. Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients. Moreover, expression of a phosphorylation-deficient PDP1 Y94F mutant in cancer cells resulted in increased oxidative phosphorylation, decreased cell proliferation under hypoxia, and reduced tumor growth in mice. Together, our findings suggest that phosphorylation at different tyrosine residues inhibits PDP1 through independent mechanisms, which act in concert to regulate PDC activity and promote the Warburg effect.
authors: From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322.
authors: Changliang
authors: C
authors: Shan
authors: From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322.
authors: Hee-Bum
authors: HB
authors: Kang
authors: From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322.
authors: Shannon
authors: S
authors: Elf
authors: Cell Signaling Technology, Inc., Danvers, Massachusetts 01923, and.
authors: Jianxin
authors: J
authors: Xie
authors: Cell Signaling Technology, Inc., Danvers, Massachusetts 01923, and.
authors: Ting-Lei
authors: TL
authors: Gu
authors: Cell Signaling Technology, Inc., Danvers, Massachusetts 01923, and.
authors: Mike
authors: M
authors: Aguiar
authors: Cell Signaling Technology, Inc., Danvers, Massachusetts 01923, and.
authors: Scott
authors: S
authors: Lonning
authors: From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322.
authors: Taro
authors: T
authors: Hitosugi
authors: From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322.
authors: Tae-Wook
authors: TW
authors: Chung
authors: From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322.
authors: Martha
authors: M
authors: Arellano
authors: From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322.
authors: Hanna J
authors: HJ
authors: Khoury
authors: From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322.
authors: Dong M
authors: DM
authors: Shin
authors: From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322.
authors: Fadlo R
authors: FR
authors: Khuri
authors: the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520.
authors: Titus J
authors: TJ
authors: Boggon
authors: From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, jfan3@emory.edu.
authors: Jun
authors: J
authors: Fan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D010101:Oxygen Consumption; D010766:Phosphorylation; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D019344:Lactic Acid; D014443:Tyrosine; D000255:Adenosine Triphosphate; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase
keywords: Cell Proliferation; Phosphoprotein Phosphatase; Phosphotyrosine Signaling; Tumor Metabolism; Warburg Effect