Anabolic PI3K/AKT signaling promotes GSK3-dependent phosphorylation and inhibition of AMPK.

  • Major finding: Anabolic PI3K/AKT signaling promotes GSK3-dependent phosphorylation and inhibition of AMPK.

  • Mechanism: AMPK phosphorylation at T479 enhances the sensitivity of the activation loop to phosphatases.

  • Impact: GSK3-mediated regulation of AMPK is critical for growth factor-induced anabolic metabolism.

Cellular energy homeostasis is maintained by AMP-activated protein kinase (AMPK) signaling, which stimulates catabolic processes and suppresses anabolic biosynthetic pathways under nutrient-poor, low-energy conditions. AMPK kinase activity is induced in response to metabolic starvation by phosphorylation within the activation loop of its catalytic α subunit; however, the mechanisms that inhibit AMPK activity under nutrient-rich conditions are unknown. Suzuki and colleagues found that glycogen synthase kinase 3 (GSK3) constitutively interacted with the AMPK β regulatory subunit and directly phosphorylated the AMPK α subunit at threonine 479 (T479) within a C-terminal serine/threonine stretch (ST-stretch). Phosphorylation of T479 did not require priming events by another kinase but was necessary for successive phosphorylation of additional residues in the ST-stretch and reduced phosphorylation of the AMPK activation loop, thus inhibiting AMPK activity. These serial modifications impaired association of the ST-stretch with the AMPK kinase domain and enhanced dephosphorylation of the activation loop by protein phosphatase 2, catalytic subunit, alpha isozyme (PP2Cα), suggesting that GSK3 triggers a conformational change that increases accessibility of phosphatases to the activation loop site. Intriguingly, treatment with insulin induced GSK3-mediated phosphorylation of T479 and subsequent dephosphorylation of the AMPK activation loop in multiple cell types, including murine heart tissue and primary hepatocytes; this suppression of AMPK catabolic activity was dependent on anabolic phosphoinositide 3-kinase (PI3K) signaling and AKT-driven phosphorylation of serine 485 within the AMPK α subunit. Furthermore, GSK3 inhibition or disruption of the T479 phosphorylation site augmented AMPK-mediated induction of catabolic pathways and impaired anabolic responses following growth factor stimulation. These results identify an essential role for GSK3-dependent inhibition of AMPK in the transition to anabolic metabolism in nutrient-rich conditions.

Suzuki T, Bridges D, Nakada D, Skiniotis G, Morrison SJ, Lin JD, et al. Inhibition of AMPK catabolic action by GSK3. Mol Cell 2013;50:417–19.

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