Authors
John Scott
Naomi Ling
Samah Issa
Toby Dite
Matthew O'Brien
Zhi-Ping Chen
Sandra Galic
Christopher Langendorf
Gregory Steinberg
Bruce Kemp
Jonathan Oakhill
Publication Date
2014
Publication Details
Scott, J., Ling, N., Issa, S., Dite, T., O'Brien, M., Chen, Z., Galic, S., Langendorf, C., Steinberg, G., Kemp, B. & Oakhill, J. (2014). Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling. Chemistry and Biology,21(5), 619-627. Retrieved from https://doi.org/10.1016/j.chembiol.2014.03.006
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.
Document Type
Journal Article
Access Rights
ERA Access