The activity of glycogen synthase kinase beta (GSK3β) is mainly regulated by its Ser9 phosphorylation. It has been believed for a long time that Ser9 phosphorylation regulates the functions of GSK3β through inhibition of its kinase activity. In this study, we have confirmed the interaction of Ser9-phosphorylated GSK3β with 14-3-3ζ by using GST pull-down assays. We show that 14-3-3ζ enhances Ser9 phosphorylation of GSK3β by PKC. Surprisingly, using a NF-κB luciferase reporter system, we find that Ser9-phosphorylation of GSK3β promoted by 14-3-3ζ is critical for the activation of NF-κB pathway, which may thwart the pro-apoptotic activity of GSK3β. Inhibition of either NF-κB or GSK3β significantly abolishes the anti-apoptotic effect of 14-3-3ζ and Ser9-phosphorylated GSK3β, suggesting that Ser9-phosphorylated GSK3β actively antagonizes cell apoptosis in a NF-κB dependent manner.
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