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B Kinase 
/
by Protein Kinase C-Dependent c-Src Activation Is Involved in TNF--Induced Cyclooxygenase-2 Expression1
* Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; and
Department of Pharmacology, National Cardiovascular Center Research Institute, Osaka, Japan
The signaling pathway involved in TNF-
-induced cyclooxygenase-2 (COX-2) expression was further studied in human NCI-H292 epithelial cells. A protein kinase C (PKC) inhibitor (staurosporine), tyrosine kinase inhibitors (genistein and herbimycin A), or a Src kinase inhibitor (PP2) attenuated TNF-- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced COX-2 promoter activity. TNF-- or TPA-induced I-
B kinase (IKK) activation was also blocked by these inhibitors, which reversed I-B degradation. Activation of c-Src and Lyn kinases, two Src family members, was inhibited by the PKC, tyrosine kinase, or Src kinase inhibitors. The dominant-negative c-Src (KM) mutant inhibited induction of COX-2 promoter activity by TNF- or TPA. Overexpression of the constitutively active PKC (PKC A/E) or wild-type c-Src plasmids induced COX-2 promoter activity, and these effects were inhibited by the dominant-negative c-Src (KM), NF-B-inducing kinase (NIK) (KA), or IKK
(KM) mutant. The dominant-negative PKC (K/R) or c-Src (KM) mutant failed to block induction of COX-2 promoter activity caused by wild-type NIK overexpression. In coimmunoprecipitation experiments, IKK/ was found to be associated with c-Src and to be phosphorylated on its tyrosine residues after TNF- or TPA treatment. Two tyrosine residues, Tyr188 and Tyr199, near the activation loop of IKK, were identified to be crucial for NF-B activation. Substitution of these residues with phenylalanines attenuated COX-2 promoter activity and c-Src-dependent phosphorylation of IKK induced by TNF- or TPA. These data suggest that, in addition to activating NIK, TNF- also activates PKC-dependent c-Src. These two pathways cross-link between c-Src and NIK and converge at IKK/, and go on to activate NF-B, via serine phosphorylation and degradation of IB-, and, finally, to initiate COX-2 expression.
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