14-3-3ζ Facilitates GSK3β-catalyzed tau phosphorylation in HEK-293 cells by a mechanism that requires phosphorylation of GSK3β on Ser9

Hyperphosphorylated tau is the prominent component of paired helical filaments, which are the major component of neurofibrillary tangles associated with Alzheimer's disease (AD). Glycogen synthase kinase 3β (GSK3β) is implicated to phosphorylate tau in normal and AD brain. Previously, we isolated a large multiprotein complex containing tau, Ser9-phosphorylated GSK3β and 14-3-3ζ from bovine brain microtubules. We showed that within the complex, 14-3-3ζ binds to tau and GSK3β and mediates GSK3β-catalyzed tau phosphorylation. A recent report however indicated that 14-3-3ζ does not bind to tau or GSK3β and does not increase tau phosphorylation by GSK3β in cell models [T.A. Matthews, G.V.W. Johnson, Neurosci. Lett. 384 (2005) 211–216]. In the current study we have thoroughly analyzed the binding of 14-3-3ζ with tau and GSK3β and evaluated the effect of 14-3-3ζ on tau phosphorylation by GSK3β in HEK-293 cells. We found that 14-3-3ζ binds to tau and Ser9-phosphorylated GSK3β. Nonphosphorylated GSK3β phosphorylates tau without being influenced by 14-3-3ζ. Ser9-phosphorylated GSK3β on the other hand phosphorylates tau significantly only in the presence of 14-3-3ζ. Our data demonstrate that 14-3-3ζ mediates tau phosphorylation by Ser9-phosphorylated GSK3β in HEK-293 cells.