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

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.
Mesh Terms:
AMP-Activated Protein Kinases, Animals, Carcinogenesis, Cell Line, Tumor, Energy Metabolism, Enzyme Inhibitors, HeLa Cells, Homeostasis, Humans, MCF-7 Cells, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Neoplasms, Protein-Serine-Threonine Kinases, Signal Transduction, Sulfones, Tankyrases, Triazoles, Xenograft Model Antitumor Assays, para-Aminobenzoates
Nat Commun
Date: Dec. 25, 2018
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