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

ChengChieh Tsai | Zendy; Jui-In Kai | Zendy; WeiChing Huang | Zendy; ChiYun Wang | Zendy; Yi Wang | Zendy; ChiaLing Chen | Zendy; Yi-Ting Fang | Zendy; Yee-Shin Lin | Zendy; Robert Anderson | Zendy; ShunHua Chen | Zendy; Chiung-Wen Tsao | Zendy; ChiouFeng Lin | Zendy

Open Access

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

Author(s) -

ChengChieh Tsai,

Jui-In Kai,

WeiChing Huang,

ChiYun Wang,

Yi Wang,

ChiaLing Chen,

Yi-Ting Fang,

Yee-Shin Lin,

Robert Anderson,

ShunHua Chen,

Chiung-Wen Tsao,

ChiouFeng Lin

Publication year - 2009

Publication title -

the journal of immunology

Language(s) - Uncategorized

Resource type - Journals

SCImago Journal Rank - 2.737

H-Index - 372

eISSN - 1550-6606

pISSN - 0022-1767

DOI - 10.4049/jimmunol.0804033

Subject(s) - gsk 3 , proto oncogene tyrosine protein kinase src , tyrosine phosphorylation , microbiology and biotechnology , phospholipase c , chemistry , phosphatase , phosphorylation , kinase , tyrosine kinase 2 , dephosphorylation , protein tyrosine phosphatase , biology , biochemistry , signal transduction , receptor , platelet derived growth factor receptor , growth factor

Glycogen synthase kinase-3beta (GSK-3beta)-modulated IFN-gamma-induced inflammation has been reported; however, the mechanism that activates GSK-3beta and the effects of activation remain unclear. Inhibiting GSK-3beta decreased IFN-gamma-induced inflammation. IFN-gamma treatment rapidly activated GSK-3beta 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-3beta 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-3beta 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-3beta synergistically affected IFN-gamma-induced STAT1 activation by inhibiting SHP2.

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