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

Agarwal-Mawal, Alka; Qureshi, Hamid Y.; Cafferty, Patrick; Yuan, Zongfei; Han, Dong Cho; Lin, Rongtian; Paudel, Helmant K.

doi:10.1074/jbc.m211491200

Cited by 170 publications

(190 citation statements)

References 47 publications

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“…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.…”

Section: Lis1 Ndel1 Nde1 and Disc1mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Section: Lis1 Ndel1 Nde1 and Disc1mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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“…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).…”

mentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

Yuan

Agarwal-Mawal

Paudel

2004

Journal of Biological Chemistry

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In mammalian brain, tau, glycogen synthase kinase 3␤ (GSK3␤), 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 GSK3␤ (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 GSK3␤ to tau within the complex is not clear. In this study, we find that GSK3␤ within the tau phosphorylation complex is phosphorylated on Ser 9 . From extracts of rat brain and rat primary cultured neurons, Ser 9 -phosphorylated GSK3␤ precipitates with glutathione-agarose beads coated with glutathione S-transferase-14-3-3. Similarly, from rat brain extract, Ser 9 -phosphorylated GSK3␤ coimmunoprecipitates with tau. In vitro, 14-3-3 binds to GSK3␤ only when the kinase is phosphorylated on Ser 9 . In transfected HEK-293 cells, 14-3-3 binds to Ser 9 -phosphorylated GSK3␤ and does not bind to GSK3␤ (S9A). Tau, on the other hand, binds to both GSK3␤ (WT) and GSK3␤ (S9A). Moreover, 14-3-3 enhances the binding of tau with Ser 9 -phosphorylated GSK3␤ by ϳ3-fold but not with GSK3␤ (S9A). Similarly, 14-3-3 stimulates phosphorylation of tau by Ser 9 -phosphorylated GSK3␤ but not by GSK3␤ (S9A). In transfected HEK-293 cells, Ser 9 phosphorylation suppresses GSK3␤-catalyzed tau phosphorylation in the absence of 14-3-3. In the presence of 14-3-3, however, Ser 9 -phosphorylated GSK3␤ remains active and phosphorylates tau. Our data indicate that within the tau phosphorylation complex, 14-3-3 connects Ser 9 -phosphorylated GSK3␤ to tau and Ser 9 -phosphorylated GSK3␤ phosphorylates tau.

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“…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.…”

Section: Discussionmentioning

confidence: 64%

“…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].…”

Section: Introductionmentioning

confidence: 96%

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

Kim

Kang

et al. 2005

Diabetologia

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Aims/hypothesis: The present study aimed to investigate the expression levels of and the relationship between 14-3-3 ζ and protein kinase C (PKC) in the retina of early diabetes. Methods: Changes in the expression levels of, and interaction between, 14-3-3 ζ and PKC were investigated by Northern and Western blot analyses, immunoprecipitation and double immunostaining in the retina of diabetic rats after 6 weeks of diabetes. PKC activity was examined using a PKC assay. Results: In the diabetic retina, the molecular levels of 14-3-3 ζ were reduced, while those of PKC β and ζ were increased. Direct interaction between 14-3-3 ζ and PKC was markedly decreased in the retina after 6 weeks of diabetes, while PKC activity was increased. Conclusions/interpretation: These findings show that a reduction in 14-3-3 ζ can induce PKC activation, suggesting that this is a main cause of visual dysfunction in the retina during diabetes.

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

Cited by 170 publications

References 47 publications

The DISC locus in psychiatric illness

The DISC locus in psychiatric illness

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

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

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