@article{ed0c12a22bed427696db85301b2f3ac6,
title = "Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling",
abstract = "The LKB1/AMPK pathway plays a major role in cellular homeostasis and tumor suppression. Down-regulation of LKB1/AMPK occurs in several human cancers and has been implicated in metabolic diseases. However, the precise upstream regulation of LKB1-AMPK pathway is largely unknown. Here, we report that AMPK activation by LKB1 is regulated by tankyrases. Tankyrases interact with and ribosylate LKB1, promoting its K63-linked ubiquitination by an E3 ligase RNF146, which blocks LKB1/STRAD/MO25 complex formation and LKB1 activation. LKB1 activation by tankyrase inhibitors induces AMPK activation and suppresses tumorigenesis. Similarly, the tankyrase inhibitor G007-LK effectively regulates liver metabolism and glycemic control in diabetic mice in a LKB1-dependent manner. In patients with lung cancer, tankyrase levels negatively correlate with p-AMPK levels and poor survival. Taken together, these findings suggest that tankyrase and RNF146 are major up-stream regulators of LKB1-AMPK pathway and provide another focus for cancer and metabolic disease therapies.",
author = "Nan Li and Yifan Wang and Shinya Neri and Yuanli Zhen and Fong, {Lon Wolf R.} and Yawei Qiao and Xu Li and Zhen Chen and Clifford Stephan and Weiye Deng and Rui Ye and Wen Jiang and Shuxing Zhang and Yonghao Yu and Hung, {Mien Chie} and Junjie Chen and Lin, {Steven H.}",
note = "Funding Information: We thank our colleagues in S.L.{\textquoteright}s laboratory for insightful discussions and assistance. We thank Christine F. Wogan at the Department of Radiation Oncology of MD Anderson Cancer Center for her expert assistance with manuscript editing. We also thank for the help from Metabolomics Facility of MD Anderson Cancer Center (funded by NIH #P30CA016672, #1S10OD012304-1 and CPRIT #RP130397). This work was supported in part by Mabuchi Program, Cancer Center Support (Core) Grant CA016672 from the National Cancer Institute, National Institutes of Health to The University of Texas MD Anderson Cancer Center. This work was also supported in part by MD Anderson Start-up funds and an Era of Hope Scholar Research award (W81XWH-09-1-0409) to J.C., and by grants from the Welch Foundation (I-1800 to Y.Y.) and NIH (GM114160 and GM122932 to Y.Y.) Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41467-019-12377-1",
language = "English (US)",
volume = "10",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}