@article{4bc84de7e31f4ca7a488ec6bc64835b3,
title = "Tyr Phosphorylation of PDP1 Toggles Recruitment between ACAT1 and SIRT3 to Regulate the Pyruvate Dehydrogenase Complex",
abstract = "Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homeostasis in mammalian cells. The current understanding of PDC regulation involves inhibitory serine phosphorylation ofpyruvate dehydrogenase (PDH) by PDH kinase (PDK), whereas dephosphorylation of PDH by PDH phosphatase (PDP) activates PDC. Here, we report that lysine acetylation of PDHA1 and PDP1 is common in epidermal growth factor (EGF)-stimulated cells and diverse human cancer cells. K321 acetylation inhibits PDHA1 by recruiting PDK1, and K202 acetylation inhibits PDP1 by dissociating its substrate PDHA1, both of which are important in promoting glycolysis in cancer cells and consequent tumor growth. Moreover, we identified mitochondrial ACAT1 and SIRT3 as the upstream acetyltransferase and deacetylase, respectively, of PDHA1 and PDP1, while knockdown of ACAT1 attenuates tumor growth. Furthermore, Y381 phosphorylation of PDP1 dissociates SIRT3 and recruits ACAT1 to PDC. Together, hierarchical, distinct posttranslational modifications act in concert to control molecular composition of PDC and contribute to the Warburg effect.",
author = "Jun Fan and Changliang Shan and Kang, {Hee Bum} and Shannon Elf and Jianxin Xie and Meghan Tucker and Gu, {Ting Lei} and Mike Aguiar and Scott Lonning and Huaibin Chen and Moosa Mohammadi and Britton, {Laura Mae P.} and Garcia, {Benjamin A.} and Ma{\v s}a Ale{\v c}kovi{\'c} and Yibin Kang and Stefan Kaluz and Narra Devi and VanMeir, {Erwin G.} and Taro Hitosugi and Seo, {Jae Ho} and Sagar Lonial and Manila Gaddh and Martha Arellano and Khoury, {Hanna J.} and Khuri, {Fadlo R.} and Boggon, {Titus J.} and Sumin Kang and Jing Chen",
note = "Funding Information: This work was supported in part by NIH grants CA140515 (J.C.), CA116804 (E.G.V.M.), the Pharmacological Sciences Training Grant T32 GM008602 (S.E.), DoD grant W81XWH-12-1-0217 (J.C.), the Samuel Waxman, Max Cure and V Foundations (E.G.V.M.), and the Hematology Tissue Bank of the Emory University School of Medicine and the Georgia Cancer Coalition (H.J.K.). J.X., M.T., T.-L.G., M. Aguiar, and S. Lonning are employees of Cell Signaling Technology, Inc. S.E. is an NIH predoctoral fellow and an ARCS Foundation Scholar. H.J.K., F.R.K., S. Kang, and J.C. are Georgia Cancer Coalition Distinguished Cancer Scholars. S. Kang is a Robbins Scholar. S. Kang and J.C. are American Cancer Society Basic Research Scholars. J.C. is a Scholar of the Leukemia and Lymphoma Society. ",
year = "2014",
month = feb,
day = "20",
doi = "10.1016/j.molcel.2013.12.026",
language = "English (US)",
volume = "53",
pages = "534--548",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "4",
}