Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase alpha-subunits in heart via hierarchical phosphorylation of Ser485/491.
Previous studies showed that insulin antagonizes AMP-activated protein kinase activation by ischemia and that protein kinase B might be implicated. Here we investigated whether the direct phosphorylation of AMP-activated protein kinase by protein kinase B might participate in this effect. Protein kinase B phosphorylated recombinant bacterially expressed AMP-activated protein kinase heterotrimers at Ser(485) of the alpha1-subunits. In perfused rat hearts, phosphorylation of the alpha1/alpha2 AMP-activated protein kinase subunits on Ser(485)/Ser(491) was increased by insulin and insulin pretreatment decreased the phosphorylation of the alpha-subunits at Thr(172) in a subsequent ischemic episode. It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser(485)/Ser(491) phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr(172) by LKB1 and the resulting activation of AMP-activated protein kinase.
Horman
Sandrine
S
Hormone and Metabolic Research Unit, Christian de Duve Institute of Cellular Pathology and Université catholique de Louvain, Avenue Hippocrate 75, B-1200 Brussels, Belgium. sandrine.horman@horm.ucl.ac.be
Vertommen
Didier
D
Heath
Richard
R
Neumann
Dietbert
D
Mouton
Véronique
V
Woods
Angela
A
Schlattner
Uwe
U
Wallimann
Theo
T
Carling
David
D
Hue
Louis
L
Rider
Mark H
MH
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D004789:Enzyme Activation; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D008297:Male; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017202:Myocardial Ischemia; D009206:Myocardium / Q000201:enzymology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism*
D007328:Insulin; D009097:Multienzyme Complexes; D021122:Protein Subunits; D013912:Threonine; D000249:Adenosine Monophosphate; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases