title: Inhibition of AMPK catabolic action by GSK3.
abstract: AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic and activating catabolic processes. While AMPK activation has been extensively studied, mechanisms that inhibit AMPK remain elusive. Here we report that glycogen synthase kinase 3 (GSK3) inhibits AMPK function. GSK3 forms a stable complex with AMPK through interactions with the AMPK β regulatory subunit and phosphorylates the AMPK α catalytic subunit. This phosphorylation enhances the accessibility of the activation loop of the α subunit to phosphatases, thereby inhibiting AMPK kinase activity. Surprisingly, PI3K-Akt signaling, which is a major anabolic signaling and normally inhibits GSK3 activity, promotes GSK3 phosphorylation and inhibition of AMPK, thus revealing how AMPK senses anabolic environments in addition to cellular energy levels. Consistently, disrupting GSK3 function within the AMPK complex sustains higher AMPK activity and cellular catabolic processes even under anabolic conditions, indicating that GSK3 acts as a critical sensor for anabolic signaling to regulate AMPK.
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Suzuki
authors.forename: Dave
authors.initials: D
authors.lastname: Bridges
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakada
authors.forename: Georgios
authors.initials: G
authors.lastname: Skiniotis
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Morrison
authors.forename: Jiandie D
authors.initials: JD
authors.lastname: Lin
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
authors.forename: Ken
authors.initials: K
authors.lastname: Inoki
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002460:Cell Line; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D021122:Protein Subunits; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases