In mammalian brain, tau, glycogen synthase kinase 3β (GSK3β), and 14-3-3, a phosphoserine-binding protein, are parts of a multiprotein tau phosphorylation complex. Within the complex, 14-3-3 simultaneously binds to tau and GSK3β (Agarwal-Mawal, A., Qureshi, H. Y., Cafferty, P. W., Yuan, Z., Han, D., Lin, R., and Paudel, H. K. (2003) J. Biol. Chem. 278, 12722-12728). The molecular mechanism by which 14-3-3 connects GSK3β to tau within the complex is not clear. In this study, we find that GSK3β within the tau phosphorylation complex is phosphorylated on Ser9. From extracts of rat brain and rat primary cultured neurons, Ser9-phosphorylated GSK3β precipitates with glutathione-agarose beads coated with glutathione S-transferase-14-3-3. Similarly, from rat brain extract, Ser9- phosphorylated GSK3β co-immunoprecipitates with tau. In vitro, 14-3-3 binds to GSK3β only when the kinase is phosphorylated on Ser9. In transfected HEK-293 cells, 14-3-3 binds to Ser9-phosphorylated GSK3β and does not bind to GSK3β (S9A). Tau, on the other hand, binds to both GSK3β (WT) and GSK3β (S9A). Moreover, 14-3-3 enhances the binding of tau with Ser9-phosphorylated GSK3β by ∼3-fold but not with GSK3β (S9A). Similarly, 14-3-3 stimulates phosphorylation of tau by Ser9-phosphorylated GSK3β but not by GSK3β (S9A). In transfected HEK-293 cells, Ser9 phosphorylation suppresses GSK3β-catalyzed tau phosphopylation in the absence of 14-3-3. In the presence of 14-3-3, however, Ser9-phosphorylated GSK3β remains active and phosphorylates tau. Our data indicate that within the tau phosphorylation complex, 14-3-3 connects Ser9-phosphorylated GSK3β to tau and Ser9-phosphorylated GSK3β phosphorylates tau.
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Yuan, Z., Agarwal-Mawal, A., & Paudel, H. K. (2004). 14-3-3 Binds to and mediates phosphorylation of microtubule-associated tau protein by Ser9-phosphorylated glycogen synthase kinase 3β in the brain. Journal of Biological Chemistry, 279(25), 26105–26114. https://doi.org/10.1074/jbc.M308298200