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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0804033v1 183/2/856    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Tsai, C.-C. Articles by Lin, C.-F. PubMed PubMed Citation Articles by Tsai, C.-C. Articles by Lin, C.-F.

Glycogen Synthase Kinase-3β Facilitates IFN--Induced STAT1 Activation by Regulating Src Homology-2 Domain-Containing Phosphatase 2¹

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^2,*,,,

^* Institute of Basic Medical Sciences and 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant NSC 96-2320-B-006-018-MY3 from the National Science Council, Taiwan, and the Landmark Project C020 of National Cheng Kung University, Taiwan.

² 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

³ Abbreviations used in this paper: GSK-3β, glycogen synthase kinase-3β; IFNGR, IFN- receptor; SOCS, suppressor of cytokine signaling; SHP2, Src homology-2 domain-containing phosphatase 2; iNOS, inducible NO synthase; IRF-1, IFN regulatory factor 1; OA, okadaic acid; PPase, protein phosphatase; SMase, sphingomyelinase; cPLA2, cytosolic phospholipase A₂; AA, arachidonic acid; DAG, diacylglycerol; Pyk2, proline-rich tyrosine kinase 2; PKC, protein kinase C; PC-PLC, phosphatidylcholine-specific phospholipase C; WT, wild type; BIO, 6-bromo-indirubin-3'-oxime; siRNA, short interference RNA; RNAi, RNA interference.

⁴ The online version of this article contains supplemental material.