Inhibition of AMPK Catabolic Action by GSK3

SummaryAMP-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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (240 K)Download as PowerPoint slideHighlights► GSK3 constitutively interacts with the AMPK complex through the β subunit ► GSK3 phosphorylates the α subunit of AMPK and inhibits its kinase activity ► The PI3K-Akt pathway enhances GSK3-dependent phosphorylation of the α subunit ► GSK3-dependent AMPK inhibition is critical for cells to enter an anabolic state