14-3-3 Connects Glycogen Synthase Kinase-3β to Tau within a Brain Microtubule-associated Tau Phosphorylation Complex

Abstract

In a recent study, we reported that in bovine brain extract, glycogen synthase kinase-3␤ and tau are parts of an ϳ400 -500 kDa microtubule-associated tau phosphorylation complex (Sun, W., Qureshi, H. Y., Cafferty, P. W., Sobue, K., Agarwal-Mawal, A., Neufield, K. D., and Paudel, H. K. (2002) J. Biol. Chem. 277, 11933-11940). In this study, we find that when purified brain microtubules are subjected to Superose 12 gel filtration column chromatography, the dimeric scaffold protein 14-3-3 coelutes with the tau phosphorylation complex components tau and GSK3␤. From gel filtration fractions containing the tau phosphorylation complex, 14-3-3, GSK3␤, and tau co-immunoprecipitate with each other. From extracts of bovine brain, COS-7 cells, and HEK-293 cells transfected with GSK3␤, 14-3-3 co-precipitates with GSK3␤, indicating that GSK3␤ binds to 14-3-3. From HEK-293 cells transfected with tau, GSK3␤, and 14-3-3 in different combinations, tau co-immunoprecipitates with GSK3␤ only in the presence of 14-3-3. In vitro, ϳ10-fold more tau binds to GSK3␤ in the presence of than in the absence of 14-3-3. In transfected HEK-293 cells, 14-3-3 stimulates GSK3␤-catalyzed tau phosphorylation in a dose-dependent manner. These data indicate that in brain, the 14-3-3 dimer simultaneously binds and bridges tau and GSK3␤ and stimulates GSK3␤-catalyzed tau phosphorylation.

The DISC locus in psychiatric illness

“…14-3-3 proteins are present in the neurofibrillary tangles associated with Alzheimer's disease 178 and may facilitate Tau hyperphosphorylation which contributes to tangle formation. 179,180 14-3-3 proteins, including 14-3-3e, also interact with a-synuclein 181 and may contribute to the pathogenesis of Parkinson's disease. Spinocerebellar ataxia type 1 results from the accumulation of mutant ataxin-1 containing polyglutamine tracts 182 and 14-3-3 isoforms, including 14-3-3e, are believed to take part in this process.…”

14-3-3 Binds to and Mediates Phosphorylation of Microtubule-associated Tau Protein by Ser9-phosphorylated Glycogen Synthase Kinase 3β in the Brain

“…GSK3␤ contains a C-terminal catalytic domain and an N-terminal regulatory loop (16,17). Phosphorylation on Ser 9 , located within the N-terminal loop, inhibits GSK3␤ activity in vitro and in various cellular settings (15,(17)(18)(19)(20)(21)(22)(23). Ser ulates GSK3␤ activity and allows glycogen synthase to escape GSK3␤-mediated inhibition (15)(16)(17)(18)(19)(20).…”

“…7 for a list). Biochemical studies have shown that GSK3␤ is physically complexed with tau in the brain and phosphorylates tau in vitro (8,9) and in vivo (10 -13). GSK3␤ is a major tau kinase in the brain (8).…”

Expression of 14-3-3 ζ and interaction with protein kinase C in the rat retina in early diabetes

“…The isotype 1 14-3-3 ζ plays a critical role in neuronal differentiation, synaptic plasticity and exocytosis [1][2][3][4][5][6]23], while PKC activation in diabetes implies diabetes-induced vascular dysfunction [14][15][16]24]. In this study, the molecular levels of 14-3-3 ζ decreased in the retina after 6 weeks of diabetes, while those of PKC β and ζ increased.…”

“…The isotype 14-3-3 ζ, along with others, has been reported to play a critical role in the central nervous system [1][2][3][4], including in neuronal differentiation [5] and synaptic plasticity [6]. Moreover, this isotype is present in significant amounts in the retina, as well as in the brain, and is necessary for light adaptation processes or differentiation in photoreceptors [7,8].…”