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
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.