@article{88086,
  keywords = {Animals, Humans, phosphorylation, Gene Expression Regulation, Enzymologic, Cell Proliferation, Mice, Male, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Glycolysis, Mitochondria, Neoplasms, Tyrosine, Mice, Nude, Lysine, Neoplasm Transplantation, Acetyl-CoA C-Acetyltransferase, Pyruvate Dehydrogenase (Lipoamide), Pyruvate Dehydrogenase (Lipoamide)-Phosphatase, Sirtuin 3},
  author = {Jun Fan and Changliang Shan and Hee-Bum Kang and Shannon Elf and Jianxin Xie and Meghan Tucker and Ting-Lei Gu and Mike Aguiar and Scott Lonning and Huaibin Chen and Moosa Mohammadi and Laura-Mae Britton and Benjamin Garcia and Ma{\v s}a Ale{\v c}kovi{\'c} and Yibin Kang and Stefan Kaluz and Narra Devi and Erwin Van Meir and Taro Hitosugi and Jae Ho Seo and Sagar Lonial and Manila Gaddh and Martha Arellano and Hanna Khoury and Fadlo Khuri and Titus Boggon and Sumin Kang and Jing Chen},
  title = {Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex.},
  abstract = {<p>Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homeostasis in mammalian cells. The current understanding of PDC regulation involves inhibitory serine phosphorylation of pyruvate 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.</p>
},
  year = {2014},
  journal = {Mol Cell},
  volume = {53},
  pages = {534-48},
  month = {02/2014},
  issn = {1097-4164},
  doi = {10.1016/j.molcel.2013.12.026},
  language = {eng},
}