@article{61c192b52d40412c850a17b4a0542ef4,
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.",
author = "Taro Hitosugi and Jun Fan and Chung, {Tae Wook} and Katherine Lythgoe and Xu Wang and Jianxin Xie and Qingyuan Ge and Gu, {Ting Lei} and Polakiewicz, {Roberto D.} and Roesel, {Johannes L.} and Chen, {Georgia Z.} and Boggon, {Titus J.} and Sagar Lonial and Haian Fu and Khuri, {Fadlo R.} and Sumin Kang and Jing Chen",
note = "Funding Information: We gratefully acknowledge the critical reading of the manuscript by Shannon Elf. We thank Hong Yi for assistance with electron microscopy. This work was supported in part by NIH grants CA120272 and CA140515 (J.C.) and Federal Funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E (H.F.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. J.X., Q.G., T.-L.G., and R.D.P. are employees of Cell Signaling Technology, Inc. J.L.R. is an employee of Novartis Pharma AG. T.H. is a Fellow Scholar of the American Society of Hematology. G.Z.C., H.F., F.R.K., S.K., and J.C. are Georgia Cancer Coalition Distinguished Cancer Scholars. S.K. is a Robbins Scholar. S.K. and J.C. are American Cancer Society Basic Research Scholars. S.K. is a Special Fellow and J.C. is a Scholar of the Leukemia and Lymphoma Society. ",
year = "2011",
month = dec,
day = "23",
doi = "10.1016/j.molcel.2011.10.015",
language = "English (US)",
volume = "44",
pages = "864--877",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}