Glycogen synthase kinase-3β facilitates IFN-γ-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, Chiou Feng Lin

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49 Citations (Scopus)

Abstract

Glycogen synthase kinase-3β(GSK-3β)-modulated IFN-γ-induced inflammation has been reported; however, the mechanism that activates GSK-3βand the effects of activation remain unclear. Inhibiting GSK-3β decreased IFN-γ-induced inflammation. IFN-γ 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-γ receptor 2-associated Jak2, but it was independent of IFN-γ 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-γ stimulation. All these results showed that activated GSK-3β synergistically affected IFN-γ-induced STAT1 activation by inhibiting SHP2.

Original languageEnglish
Pages (from-to)856-864
Number of pages9
JournalJournal of Immunology
Volume183
Issue number2
DOIs
Publication statusPublished - Jul 15 2009

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ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Tsai, C-C., Kai, J-I., Huang, W-C., Wang, C-Y., Wang, Y., Chen, C-L., Fang, Y-T., Lin, Y-S., Anderson, R., Chen, S-H., Tsao, C-W., & Lin, C. F. (2009). Glycogen synthase kinase-3β facilitates IFN-γ-induced STAT1 activation by regulating Src homology-2 domain-containing phosphatase 2. Journal of Immunology, 183(2), 856-864. https://doi.org/10.4049/jimmunol.0804033