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Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling

Author

Listed:
  • Nan Li

    (The University of Texas MD Anderson Cancer Center)

  • Yifan Wang

    (The University of Texas MD Anderson Cancer Center
    The University of Texas Graduate School of Biomedical Sciences Houston
    University of Texas Southwestern Medical Center)

  • Shinya Neri

    (The University of Texas MD Anderson Cancer Center)

  • Yuanli Zhen

    (University of Texas Southwestern Medical Center)

  • Lon Wolf R. Fong

    (The University of Texas Graduate School of Biomedical Sciences Houston
    The University of Texas MD Anderson Cancer Center)

  • Yawei Qiao

    (The University of Texas MD Anderson Cancer Center)

  • Xu Li

    (The University of Texas MD Anderson Cancer Center
    Westlake University)

  • Zhen Chen

    (The University of Texas MD Anderson Cancer Center)

  • Clifford Stephan

    (The Institute of Biosciences and Technology at Texas A&M University)

  • Weiye Deng

    (University of Texas Southwestern Medical Center
    The University of Texas MD Anderson Cancer Center)

  • Rui Ye

    (The University of Texas MD Anderson Cancer Center
    The University of Texas Graduate School of Biomedical Sciences Houston)

  • Wen Jiang

    (University of Texas Southwestern Medical Center
    The University of Texas MD Anderson Cancer Center)

  • Shuxing Zhang

    (The University of Texas MD Anderson Cancer Center)

  • Yonghao Yu

    (University of Texas Southwestern Medical Center)

  • Mien-Chie Hung

    (The University of Texas Graduate School of Biomedical Sciences Houston
    The University of Texas MD Anderson Cancer Center)

  • Junjie Chen

    (The University of Texas MD Anderson Cancer Center
    The University of Texas Graduate School of Biomedical Sciences Houston)

  • Steven H. Lin

    (The University of Texas MD Anderson Cancer Center
    The University of Texas Graduate School of Biomedical Sciences Houston
    The University of Texas MD Anderson Cancer Center)

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.

Suggested Citation

  • Nan Li & Yifan Wang & Shinya Neri & Yuanli Zhen & Lon Wolf R. Fong & Yawei Qiao & Xu Li & Zhen Chen & Clifford Stephan & Weiye Deng & Rui Ye & Wen Jiang & Shuxing Zhang & Yonghao Yu & Mien-Chie Hung &, 2019. "Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12377-1
    DOI: 10.1038/s41467-019-12377-1
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