Glycogen synthase kinase-3β phosphorylates tau protein at multiple sites in intact cells

Sperber, Brian R.; Leight, Susan; Goedert, Michel; Lee, V. M.-Y.

doi:10.1016/0304-3940(95)11902-9

Cited by 203 publications

(131 citation statements)

References 19 publications

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“…In vitro kinase assays 67,68 were preformed as previously described with slight modification. Three micromoles of recombinant human α-Syn (hα-Syn), 1-140 aa (R-peptide, Bogart, GA, USA), or recombinant human Tau-2N4R (hTau-2N4R) (R-peptide), were incubated with 33.0 nM of the following individual kinases; recombinant human GSK-3β (hGSK-3β) (Promega, Madison, WI, USA), human polo-like kinase-2 (hPLK2) (Carna Biosciences, Natick, MA, USA), casein kinase-2 (hCK2) (Millipore), or human G-protein-coupled receptor kinase-5 (hGRK5) (MBL, Woburn, MA, USA) in 50 μl of kinase buffer (25 mM MOPS, pH 7.2, 12.5 mM β-glycerol-phosphate, 25 mM MgCl 2 , 5 mM EGTA, and 2 mM EDTA) supplemented with 0.2 mM ATP, 50 μM DTT at 25°C for indicated times.…”

Section: Diffusion Tensor Mri Mri Was Performed At the Preclinical Imentioning

confidence: 99%

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

et al. 2014

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Aberrant posttranslational modifications (PTMs) of proteins, namely phosphorylation, induce abnormalities in the biological properties of recipient proteins, underlying neurological diseases including Parkinson's disease (PD). Genome-wide studies link genes encoding α-synuclein (α-Syn) and Tau as two of the most important in the genesis of PD. Although several kinases are known to phosphorylate α-Syn and Tau, we focused our analysis on GSK-3β because of its accepted role in phosphorylating Tau and to increasing evidence supporting a strong biophysical relationship between α-Syn and Tau in PD. Therefore, we investigated transgenic mice, which express a point mutant (S9A) of human GSK-3β. GSK-3β-S9A is capable of activation through endogenous natural signaling events, yet is unable to become inactivated through phosphorylation at serine-9. We used behavioral, biochemical, and in vitro analysis to assess the contributions of GSK-3β to both α-Syn and Tau phosphorylation. Behavioral studies revealed progressive age-dependent impairment of motor function, accompanied by loss of tyrosine hydroxylase-positive (TH+ DA-neurons) neurons and dopamine production in the oldest age group. Magnetic resonance imaging revealed deterioration of the substantia nigra in aged mice, a characteristic feature of PD patients. At the molecular level, kinase-active p-GSK-3β-Y216 was seen at all ages throughout the brain, yet elevated levels of p-α-Syn-S129 and p-Tau (S396/404) were found to increase with age exclusively in TH+ DA-neurons of the midbrain. p-GSK-3β-Y216 colocalized with p-Tau and p-α-Syn-S129. In vitro kinase assays showed that recombinant human GSK-3β directly phosphorylated α-Syn at a single site, Ser129, in addition to its known ability to phosphorylate Tau. Moreover, α-Syn and Tau together cooperated with one another to increase the magnitude or rate of phosphorylation of the other by GSK-3β. Together, these data establish a novel upstream role for GSK-3β as one of several kinases associated with PTMs of key proteins known to be causal in PD.

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Section: Diffusion Tensor Mri Mri Was Performed At the Preclinical Imentioning

confidence: 99%

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

et al. 2014

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“…Further, growth factor-triggered inactivation of GSK-3b by PI3K signaling acts through APC to control axon elongation (Zhou et al 2004). Two other GSK-3 targets, the microtubule associated proteins (MAPs) MAP1b (Gonzalez-Billault et al 2004) and Tau (Sperber et al 1995), display reduced microtubule binding when phosphorylated by GSK-3. These results emphasize that the microtubule cytoskeleton is a major endpoint for polarity regulators.…”

Section: Microtubule Dynamics and Axon Elongationmentioning

confidence: 99%

Initiating and Growing an Axon

Polleux¹,

Snider²

2010

Cold Spring Harbor Perspectives in Biology

163

127

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The ability of neurons to form a single axon and multiple dendrites underlies the directional flow of information transfer in the central nervous system. Dendrites and axons are molecularly and functionally distinct domains. Dendrites integrate synaptic inputs, triggering the generation of action potentials at the level of the soma. Action potentials then propagate along the axon, which makes presynaptic contacts onto target cells. This article reviews what is known about the cellular and molecular mechanisms underlying the ability of neurons to initiate and extend a single axon during development. Remarkably, neurons can polarize to form a single axon, multiple dendrites, and later establish functional synaptic contacts in reductionist in vitro conditions. This approach became, and remains, the dominant model to study axon initiation and growth and has yielded the identification of many molecules that regulate axon formation in vitro (Dotti et al. 1988). At present, only a few of the genes identified using in vitro approaches have been shown to be required for axon initiation and outgrowth in vivo. In vitro, axon initiation and elongation are largely intrinsic properties of neurons that are established in the absence of relevant extracellular cues. However, the importance of extracellular cues to axon initiation and outgrowth in vivo is emerging as a major theme in neural development (Barnes and Polleux 2009). In this article, we focus our attention on the extracellular cues and signaling pathways required in vivo for axon initiation and axon extension.

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“…Glycogen synthase kinase 3 beta (GSK3␤) has been shown to phosphorylate tau in vitro, in cells and in neurons at sites that are phosphorylated in PHF. [4][5][6] Several groups 7,8 have shown that there is an increase in GSK3␤ levels in AD brain and that it is found to be associated with PHF. 7,9 GSK3␤ also binds to the presenilin 1 protein, 10 it is a critical intermediate in the wnt signalling pathway suggested to be altered in AD 11 and in the insulin signalling cascade, also possibly altered in AD.…”

mentioning

confidence: 99%

Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 β gene and promoter in late onset Alzheimer's disease

Russ¹,

Lovestone²,

Powell³

2001

Mol Psychiatry

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Alzheimer's disease (AD) is a disorder characterised by a progressive deterioration in memory and other cognitive functions. Glycogen synthase kinase 3 beta (GSK3␤) phosphorylates the microtubule associated protein tau at sites that are aberrantly phosphorylated in AD. GSK3␤ binds to presenilin 1 and plays a role in wnt and insulin signalling cascades, both of which have been proposed to be linked to AD. Moreover GSK3␤ activity may be altered in AD brain. These observations suggest a central role for GSK3␤ in AD and led us to investigate GSK3␤ as a candidate gene for AD. We sought to identify sequence variations in the gene and its promoter, as these could have an effect on activity and expression leading to abnormal function. Sequencing over 3000 bp of the GSK3␤ putative promoter revealed there to be five sequence variations, two of which were common (Ͼ10%). However on further examination none of these, either alone or in synergy, had any association with late onset AD. Stratification of the data by APOE ⑀4 status also produced no significant association. Sequencing of the GSK3␤ coding region revealed no variations. This would suggest that the aberrant phosphorylation of tau by GSK3␤ in AD is not due to sequence variations in the gene or its promoter. Molecular Psychiatry (2001) 6, 320-324.

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Glycogen synthase kinase-3β phosphorylates tau protein at multiple sites in intact cells

Cited by 203 publications

References 19 publications

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

Initiating and Growing an Axon

Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 β gene and promoter in late onset Alzheimer's disease

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