AMP as a low-energy charge signal autonomously initiates assembly of AXIN-AMPK-LKB1 complex for AMPK activation

Cell Metab. 2013 Oct 1;18(4):546-55. doi: 10.1016/j.cmet.2013.09.005.

Abstract

The AMP-activated protein kinase (AMPK) is a master regulator of metabolic homeostasis by sensing cellular energy status. AMPK is mainly activated via phosphorylation by LKB1 when cellular AMP/ADP levels are increased. However, how AMP/ADP brings about AMPK phosphorylation remains unclear. Here, we show that it is AMP, but not ADP, that drives AXIN to directly tether LKB1 to phosphorylate AMPK. The complex formation of AXIN-AMPK-LKB1 is greatly enhanced in glucose-starved or AICAR-treated cells and in cell-free systems supplemented with exogenous AMP. Depletion of AXIN abrogated starvation-induced AMPK-LKB1 colocalization. Importantly, adenovirus-based knockdown of AXIN in the mouse liver impaired AMPK activation and caused exacerbated fatty liver after starvation, underscoring an essential role of AXIN in AMPK activation. These findings demonstrate an initiating role of AMP and demonstrate that AXIN directly transmits AMP binding of AMPK to its activation by LKB1, uncovering the mechanistic route for AMP to elicit AMPK activation by LKB1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / deficiency
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Acetyl-CoA Carboxylase / metabolism
  • Adenosine Monophosphate / metabolism
  • Adenosine Monophosphate / pharmacology*
  • Animals
  • Axin Protein / antagonists & inhibitors
  • Axin Protein / genetics
  • Axin Protein / metabolism*
  • Cell Line
  • Cell-Free System
  • Enzyme Activation
  • HEK293 Cells
  • Humans
  • Lipid Metabolism / physiology
  • Liver / cytology
  • Liver / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Phosphorylation / drug effects
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / genetics
  • Signal Transduction / drug effects*

Substances

  • Axin Protein
  • RNA, Small Interfering
  • Recombinant Proteins
  • Adenosine Monophosphate
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase