Ser9-phosphorylated GSK3β induced by 14-3-3ζ actively antagonizes cell apoptosis in a NF-κB dependent manner

The activity of glycogen synthase kinase beta (GSK3 beta) is mainly regulated by its Ser9 phosphorylation. It has been believed for a long time that Ser9 phosphorylation regulates the functions of GSK3 beta through inhibition of its kinase activity. In this study, we have confirmed the interaction of Ser9-phosphorylated GSK3 beta with 14-3-3 zeta by using GST pull-down assays. We show that 14-3-3 zeta enhances Ser9 phosphorylation of GSK3 beta by PKC. Surprisingly, using a NF-kappa B luciferase reporter system, we find that Ser9-phosphorylation of GSK3 beta promoted by 14-3-3 zeta is critical for the activation of NF-kappa B pathway, which may thwart the pro-apoptotic activity of GSK3 beta. Inhibition of either NF-kappa B or GSK3 beta significantly abolishes the anti-apoptotic effect of 14-3-3 zeta and Ser9-phosphorylated GSK3 beta, suggesting that Ser9-phosphorylated GSK3 beta actively antagonizes cell apoptosis in a NF-kappa B dependent manner.