AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits.

TY - JOUR

T1 - AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits.

AU - Treebak, Jonas T

AU - Glund, Stephan

AU - Deshmukh, Atul

AU - Klein, Ditte K

AU - Long, Yun Chau

AU - Jensen, Thomas E

AU - Jørgensen, Sebastian B

AU - Viollet, Benoit

AU - Andersson, Leif

AU - Neumann, Dietbert

AU - Wallimann, Theo

AU - Richter, Erik A

AU - Chibalin, Alexander V

AU - Zierath, Juleen R

AU - Wojtaszewski, Jørgen F P

N1 - Keywords: Adenylate Kinase; Aminoimidazole Carboxamide; Animals; Biological Transport; Catalysis; GTPase-Activating Proteins; Glucose; Insulin; Kinetics; Mice; Mice, Knockout; Muscle, Skeletal; Phosphorylation; Protein Subunits; Ribonucleotides

PY - 2006

Y1 - 2006

N2 - AMP-activated protein kinase (AMPK) is a heterotrimeric protein that regulates glucose transport mediated by cellular stress or pharmacological agonists such as 5-aminoimidazole-4-carboxamide 1 beta-d-ribonucleoside (AICAR). AS160, a Rab GTPase-activating protein, provides a mechanism linking AMPK signaling to glucose uptake. We show that AICAR increases AMPK, acetyl-CoA carboxylase, and AS160 phosphorylation by insulin-independent mechanisms in isolated skeletal muscle. Recombinant AMPK heterotrimeric complexes (alpha1beta1gamma1 and alpha2beta2gamma1) phosphorylate AS160 in a cell-free assay. In mice deficient in AMPK signaling (alpha2 AMPK knockout [KO], alpha2 AMPK kinase dead [KD], and gamma3 AMPK KO), AICAR effects on AS160 phosphorylation were severely blunted, highlighting that complexes containing alpha2 and gamma3 are necessary for AICAR-stimulated AS160 phosphorylation in intact skeletal muscle. Contraction-mediated AS160 phosphorylation was also impaired in alpha2 AMPK KO and KD but not gamma3 AMPK KO mice. Our results implicate AS160 as a downstream target of AMPK.

AB - AMP-activated protein kinase (AMPK) is a heterotrimeric protein that regulates glucose transport mediated by cellular stress or pharmacological agonists such as 5-aminoimidazole-4-carboxamide 1 beta-d-ribonucleoside (AICAR). AS160, a Rab GTPase-activating protein, provides a mechanism linking AMPK signaling to glucose uptake. We show that AICAR increases AMPK, acetyl-CoA carboxylase, and AS160 phosphorylation by insulin-independent mechanisms in isolated skeletal muscle. Recombinant AMPK heterotrimeric complexes (alpha1beta1gamma1 and alpha2beta2gamma1) phosphorylate AS160 in a cell-free assay. In mice deficient in AMPK signaling (alpha2 AMPK knockout [KO], alpha2 AMPK kinase dead [KD], and gamma3 AMPK KO), AICAR effects on AS160 phosphorylation were severely blunted, highlighting that complexes containing alpha2 and gamma3 are necessary for AICAR-stimulated AS160 phosphorylation in intact skeletal muscle. Contraction-mediated AS160 phosphorylation was also impaired in alpha2 AMPK KO and KD but not gamma3 AMPK KO mice. Our results implicate AS160 as a downstream target of AMPK.

U2 - 10.2337/db06-0175

DO - 10.2337/db06-0175

M3 - Journal article

C2 - 16804075

SN - 0012-1797

VL - 55

SP - 2051

EP - 2058

JO - Diabetes

JF - Diabetes

IS - 7

ER -