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14-3-3 Binds to and Mediates Phosphorylation of Microtubule-associated Tau Protein by Ser 9 -phosphorylated Glycogen Synthase Kinase 3β in the Brain *

Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 279, Issue: 25, Page: 26105-26114
2004
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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 Ser 9. From extracts of rat brain and rat primary cultured neurons, Ser 9 -phosphorylated GSK3β precipitates with glutathione-agarose beads coated with glutathione S -transferase-14-3-3. Similarly, from rat brain extract, Ser 9 -phosphorylated GSK3β co-immunoprecipitates with tau. In vitro, 14-3-3 binds to GSK3β only when the kinase is phosphorylated on Ser 9. In transfected HEK-293 cells, 14-3-3 binds to Ser 9 -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 Ser 9 -phosphorylated GSK3β by ∼3-fold but not with GSK3β (S9A). Similarly, 14-3-3 stimulates phosphorylation of tau by Ser 9 -phosphorylated GSK3β but not by GSK3β (S9A). In transfected HEK-293 cells, Ser 9 phosphorylation suppresses GSK3β-catalyzed tau phosphorylation in the absence of 14-3-3. In the presence of 14-3-3, however, Ser 9 -phosphorylated GSK3β remains active and phosphorylates tau. Our data indicate that within the tau phosphorylation complex, 14-3-3 connects Ser 9 -phosphorylated GSK3β to tau and Ser 9 -phosphorylated GSK3β phosphorylates tau.

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