Table 1. Regulation of GSK-3 Activity by Multiple Mechanisms.

GSK-3 is regulated by a wide variety of mechanisms. Inhibitory mechanisms include N-terminal phosphorylation and sequestration of GSK-3 by binding proteins. Stimulatory mechanisms include tyrosine phosphorylation and increased substrate access through scaffolding proteins. GSK-3 shows a marked preference for phosphorylated substrates and several molecules can change GSK-3 intracellular location, although the functional consequences of this are still under investigation. Finally, GSK-3 can autoregulate through the PP-1/I-2 complex I where stimulus-induced changes in GSK-3 activity can be magnified.

Regulation Method	Location of Regulation	Activity Change	Detailed Notes
Protein phosphorylation	N-terminal phosphorylation	Reduced activity	Ser9 in GSK-3β and Ser21 in GSK-3α
Protein phosphorylation	Tyrosine phosphorylation	Increased activity	Tyr216 in GSK3β and Tyr279 in GSK3α
Protein complex	GSK-3 binding proteins	Reduced activity	Sequester GSK-3
Protein complex	Scaffolding proteins	Increased activity	Catalyze GSK-3 and substrate binding
Substrate preference	Phosphorylated substrates	Increased activity	100-1000 times more efficient on primed substrates
Cellular localization	Nucleus	Unknown	Latent nuclear antigen
Cellular localization	Cytosol	Unknown	FRAT 1,2
Autoregulation	PP-1 to Ser9	Amplified activity	PP-1/I-2 complex I