Figure 3.

Regulation of UPS components by AMPK. A, Activation of AMPK using AICAR in cell culture models leads to increased activity of the FoxO1/3 and MEF-2 transcription factors, which up-regulate the expression of the E3 ubiquitin ligase atrogenes MuRF1 and Atrogin-1 and subsequent degradation of atrogene substrates. B, AMPK affects the activity of the Laforin/Malin E3 ligase complex and regulation/degradation of the glycogen-associated protein PTG. AMPK phosphorylates Ser25 on Laforin, promoting the association between Laforin and Malin. AMPK also phosphorylates PTG, which decreases PTG protein stability by promoting recognition and canonical ubiquitination (red) by Malin. Malin polyubiquitinates Laforin under low glucose conditions, and Malin also polyubiquitinates AMPK with stabilizing, noncanonical K63-linked chains (yellow). C, AMPK phosphorylates and activates the E3 ubiquitin ligase Nedd4-2, which polyubiquitinates a variety of membrane-associated transporters resulting in transporter removal from the plasma membrane and the reduction of membrane transport activity.