Glycogen synthase kinase-3beta facilitates IFN-gamma-induced STAT1 activation by regulating Src homology-2 domain-containing phosphatase 2.
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.
Tsai
Cheng-Chieh
CC
Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.
Kai
Jui-In
JI
Huang
Wei-Ching
WC
Wang
Chi-Yun
CY
Wang
Yi
Y
Chen
Chia-Ling
CL
Fang
Yi-Ting
YT
Lin
Yee-Shin
YS
Anderson
Robert
R
Chen
Shun-Hua
SH
Tsao
Chiung-Wen
CW
Lin
Chiou-Feng
CF
D000818:Animals; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D007249:Inflammation / Q000188:drug therapy; D007371:Interferon-gamma / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors*; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; D051418:Focal Adhesion Kinase 2; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C