TY - JOUR
T1 - Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling
AU - Scott, John W.
AU - Ling, Naomi
AU - Issa, Samah M.A.
AU - Dite, Toby A.
AU - O'Brien, Matthew T.
AU - Chen, Zhi Ping
AU - Galic, Sandra
AU - Langendorf, Christopher G.
AU - Steinberg, Gregory R.
AU - Kemp, Bruce E.
AU - Oakhill, Jonathan S.
N1 - Funding Information:
We thank F. Katsis for the preparation of antibodies and J. Gordon (Washington University) for N-myristoyltransferase construct. This work was supported by grants and fellowships from the Australian Research Council and the National Health and Medical Research Council (J.S.O., B.E.K., and J.W.S.). this work was supported in part by the Victorian Government’s Operational Infrastructure Support Program.
PY - 2014/5/22
Y1 - 2014/5/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84901329684&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2014.03.006
DO - 10.1016/j.chembiol.2014.03.006
M3 - Article
C2 - 24746562
AN - SCOPUS:84901329684
SN - 1074-5521
VL - 21
SP - 619
EP - 627
JO - Chemistry & Biology
JF - Chemistry & Biology
IS - 5
ER -
