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

Cheng-Chieh Tsai^*,,, Jui-In Kai^,, Wei-Ching Huang^*,,, Chi-Yun Wang^*,, Yi Wang^,, Chia-Ling Chen, Yi-Ting Fang^*,, Yee-Shin Lin^*,,¶, Robert Anderson^||, Shun-Hua Chen^*,, Chiung-Wen Tsao and Chiou-Feng Lin^*,,,

^*Institute of Basic Medical Sciences Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan; Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan; Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan; ^¶Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, Taiwan; and ^||Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada

Glycogen synthase kinase-3β (GSK-3β)-modulated IFN--induced inflammation has been reported; however, the mechanism that activates GSK-3β and the effects of activation remain unclear. Inhibiting GSK-3β decreased IFN--induced inflammation. IFN- treatment rapidly activated GSK-3β via neutral sphingomyelinase- and okadaic acid-sensitive phosphatase-regulated dephosphorylation at Ser⁹, and proline-rich tyrosine kinase 2 (Pyk2)-regulated phosphorylation at Tyr²¹⁶. 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-3β was potentially regulated by IFN- receptor 2-associated Jak2, but it was independent of IFN- receptor 1. Furthermore, Jak2/PC-PLC/PKC/cytosolic phospholipase A₂ positively regulated neutral sphingomyelinase. Inhibiting GSK-3β activated Src homology-2 domain-containing phosphatase 2 (SHP2), thereby preventing STAT1 activation in the late stage of IFN- stimulation. All these results showed that activated GSK-3β synergistically affected IFN--induced STAT1 activation by inhibiting SHP2.

Address correspondence and reprint requests to Dr. Chiou-Feng Lin, Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 701, Taiwan. E-mail address: cflin{at}mail.ncku.edu.tw