Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling. Academic Article uri icon

abstract

  • The LKB1/AMPK pathway plays amajor 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.

published proceedings

  • Nat Commun

altmetric score

  • 5.1

author list (cited authors)

  • Li, N., Wang, Y., Neri, S., Zhen, Y., Fong, L., Qiao, Y., ... Lin, S. H.

citation count

  • 49

complete list of authors

  • Li, Nan||Wang, Yifan||Neri, Shinya||Zhen, Yuanli||Fong, Lon Wolf R||Qiao, Yawei||Li, Xu||Chen, Zhen||Stephan, Clifford||Deng, Weiye||Ye, Rui||Jiang, Wen||Zhang, Shuxing||Yu, Yonghao||Hung, Mien-Chie||Chen, Junjie||Lin, Steven H

publication date

  • January 2019