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Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling
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Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling
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Journal Article
Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling
2019
Overview
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.
The LKB1/AMPK is crucial for maintaining cellular homeostasis and is often deregulated in tumours. Here, the authors show that the ribosylation of LKB1 by tankyrase-RNF146 axis results in attenuation of LKB1 pathway activation.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/95
/ 631/67
/ 64
/ 64/60
/ 96
/ 96/95
/ AMP-Activated Protein Kinase Kinases
/ AMP-Activated Protein Kinases - antagonists & inhibitors
/ AMP-Activated Protein Kinases - metabolism
/ Animals
/ Carcinogenesis - drug effects
/ Energy Metabolism - drug effects
/ Enzyme Inhibitors - pharmacology
/ Glucose
/ Humanities and Social Sciences
/ Humans
/ para-Aminobenzoates - pharmacology
/ Protein Serine-Threonine Kinases - antagonists & inhibitors
/ Protein Serine-Threonine Kinases - metabolism
/ Science
/ Signal Transduction - drug effects
/ Signal Transduction - genetics
