Glycogen Synthase Kinase-3β Facilitates IFN-γ-Induced STAT1 Activation by Regulating Src Homology-2 Domain-Containing Phosphatase 2

Glycogen synthase kinase-3 beta (GSK-3 beta)-modulated IFN-gamma-induced inflammation has been reported; however, the mechanism that activates GSK-3 beta and the effects of activation remain unclear. Inhibiting GSK-3 beta decreased IFN-gamma-induced inflammation. IFN-gamma treatment rapidly activated GSK-3 beta via neutral sphingomyelinase- and okadaic acid-sensitive phosphatase-regulated dephosphorylation at Ser(9), and proline-rich tyrosine kinase 2 (Pyk2)-regulated phosphorylation at Tyr(216). Pyk2 was activated through phosphatidylcholine-specific phospholipase C (PC-PLC)-, protein kinase C (PKC)-, and Src-regulated pathways. The activation of PC-PLC, Pyk2, and GSK-3 beta was potentially regulated by IFN-gamma receptor 2-associated Jak2, but it was independent of IFN-gamma receptor 1. Furthermore, Jak2/PC-PLC/PKC/cytosolic phospholipase A(2) positively regulated neutral sphingomyelinase. Inhibiting GSK-3 beta activated Src homology-2 domain-containing phosphatase 2 (SHP2), thereby preventing STAT1 activation in the late stage of IFN-gamma stimulation. All these results showed that activated GSK-3 beta synergistically affected IFN-gamma-induced STAT1 activation by inhibiting SHP2. The Journal of Immunology, 2009, 183: 856-864.