Small Molecule Drug A-769662 and AMP Synergistically Activate Naive AMPK Independent of Upstream Kinase Signaling Academic Article uri icon

  •  
  • Overview
  •  
  • Research
  •  
  • Identity
  •  
  • Additional Document Info
  •  
  • View All
  •  

abstract

  • The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αβγ heterotrimer responsible for energy homeostasis, making it a therapeutic target for metabolic diseases such as type 2 diabetes and obesity. AMPK signaling is triggered by phosphorylation on the AMPK α subunit activation loop Thr172 by upstream kinases. Dephosphorylated, naive AMPK is thought to be catalytically inactive and insensitive to allosteric regulation by AMP and direct AMPK-activating drugs such as A-769662. Here we show that A-769662 activates AMPK independently of α-Thr172 phosphorylation, provided β-Ser108 is phosphorylated. Although neither A-769662 nor AMP individually stimulate the activity of dephosphorylated AMPK, together they stimulate >1,000-fold, bypassing the requirement for β-Ser108 phosphorylation. Consequently A-769662 and AMP together activate naive AMPK entirely allosterically and independently of upstream kinase signaling. These findings have important implications for development of AMPK-targeting therapeutics and point to possible combinatorial therapeutic strategies based on AMP and AMPK drugs.

authors

  • Scott, John W
  • Ling, Naomi
  • Issa, Samah MA
  • Dite, Toby A
  • O’Brien, Matthew T
  • Chen, Zhi-Ping
  • Galic, Sandra
  • Langendorf, Christopher G
  • Steinberg, Gregory
  • Kemp, Bruce E
  • Oakhill, Jonathan S

publication date

  • May 2014

has subject area