Figure 3.

Positive feedback regulation of GSK-3 through β-arrestin-2 and PP1. GSK-3 regulates its own activity by modulating its N-terminal phosphorylation state. As shown in Figure 2, GSK-3 enhances stability of the β-arrestin-2 scaffold, leading to inactivation of Akt, and thereby reducing GSK-3 phosphorylation. In addition, PP1 dephosphorylates and activates GSK-3, but is inhibited by the PP1-specific inhibitor-2 (I-2). GSK-3 inactivates I-2, preventing PP1 inhibition, and thereby maintaining dephosphorylation of GSK-3. Thus GSK-3 activity is regulated by positive feedback loops involving β-arrestin-2 and PP1.