Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The substrate specificity of glycogen synthase kinase 3 (GSK3) is unusual in that efficient phosphorylation only occurs if another phosphoserine or phosphothreonine residue is already present four residues C-terminal to the site of GSK3 phosphorylation. One such substrate is the epsilon-subunit of rat eukaryotic protein-synthesis initiation factor 2B (eIF2Bepsilon), which is inhibited by the GSK3-catalysed phosphorylation of Ser(535). There is evidence that GSK3 is only able to phosphorylate eIF2Bepsilon at Ser(535) if Ser(539) is already phosphorylated by another protein kinase. However, no protein kinases capable of phosphorylating Ser(539) have so far been identified. Here we show that Ser(539) of eIF2Bepsilon, which is followed by proline, is phosphorylated specifically by two isoforms of dual-specificity tyrosine phosphorylated and regulated kinase (DYRK2 and DYRK1A), but only weakly or not at all by other 'proline-directed' protein kinases tested. We also establish that phosphorylation of Ser(539) permits GSK3 to phosphorylate Ser(535) in vitro and that eIF2Bepsilon is highly phosphorylated at Ser(539) in vivo. The DYRK isoforms also phosphorylate human microtubule-associated protein tau at Thr(212) in vitro, a residue that is phosphorylated in foetal tau and hyperphosphorylated in filamentous tau from Alzheimer's-disease brain. Phosphorylation of Thr(212) primes tau for phosphorylation by GSK3 at Ser(208) in vitro, suggesting a more general role for DYRK isoforms in priming phosphorylation of GSK3 substrates.
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PMID:The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. 1131 Nov 21

The microtubule-associated protein, tau, is the principal component of paired helical filaments (PHFs) in Alzheimer's disease. PHF-tau is highly phosphorylated and a total of 25 sites of phosphorylation have so far been identified. Many of these sites are serine or threonine residues that are immediately followed in the sequence by proline residues, and hence are candidate phosphorylation sites for proline-directed kinases. In vitro, glycogen synthase kinase-3 (GSK-3), extracellular signal-related kinase-1 and -2, and mitogen-activated protein kinases, p38 kinase and c-jun N-terminal kinase, all phosphorylate many of these sites, although with different efficiencies for particular sites. Phosphorylation studies in transfected cells and neurons show that GSK-3 phosphorylates tau more extensively than do these other proline-directed kinases. Mutations in tau have been shown to affect in vitro phosphorylation of tau by GSK-3. The Arg406-->Trp (R406W) tau mutation also affects tau phosphorylation in cells.
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PMID:Sites of phosphorylation in tau and factors affecting their regulation. 1144 41

A hallmark of several neurodegenerative disorders, including Alzheimer's disease and tauopathies, is the hyperphosphorylation of the microtubule-associated protein tau. Tau phosphorylation by proline-directed and non-proline-directed protein kinases has been tested using antibodies PHF1 and 12E8, respectively. The effect of the lipid peroxidation product acrolein on these modes of phosphorylation has been assayed. We have found that acrolein, a peroxidation product from arachidonic acid, increases the phosphorylation of tau at the site recognized by PHF-1 both in human neuroblastoma cells and in primary cultures of mouse embryo cortical neurons. Whereas the basal phosphorylation of tau protein at the PHF1 site seems to be largely mediated by glycogen synthase kinase-3 (which is also activated in response to Abeta peptide), the acrolein-induced tau hyperphosphorylation at the same site is also due to p38 stress-activated kinase. These results support the view that oxidative stress and subsequent formation of lipid peroxidation products may contribute to tau protein phosphorylation in Alzheimer's disease and tauopathies.
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PMID:Effect of the lipid peroxidation product acrolein on tau phosphorylation in neural cells. 1260 13

The Alzheimer's disease pathogenic peptide, beta-amyloid42 (A beta 42), induces tau protein phosphorylation. Because hyperphosphorylated tau is a consistent component of neurofibrillary tangles, a pathological hallmark of Alzheimer's disease, we investigated the signaling molecules involved in A beta 42-induced tau phosphorylation. We show that A beta 42 elicited rapid and reversible tau protein phosphorylation on three proline-directed sites (Ser-202, Thr-181, and Thr-231) in systems enriched in alpha 7 nicotinic acetylcholine receptors (alpha 7nAChR) including serum-deprived human SK-N-MC neuroblastoma cells and hippocampal synaptosomes. Although alpha 7nAChR agonists induced similar phosphorylation, pretreatment with antisense-alpha 7nAChR oligonucleotides (in cells) or alpha 7nAChR antagonists (in cells and synaptosomes) attenuated A beta-induced tau phosphorylation. Western analyses showed that the mitogen-activated kinase cascade proteins, ERKs and c-Jun N-terminal kinase (JNK-1), were concomitantly activated by A beta 42, and their respective kinase inhibitors suppressed A beta-induced tau phosphorylation. More importantly, recombinant-activated ERKs and JNK-1 could differentially phosphorylate tau protein in vitro. Thus, the alpha 7nAChR may mediate A beta-induced tau protein phosphorylation via ERKs and JNK-1.
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PMID:Alpha 7 nicotinic acetylcholine receptors mediate beta-amyloid peptide-induced tau protein phosphorylation. 1280 34

Neurofilaments are neuron-specific intermediate filaments. They are classed into three groups according to their molecular masses: neurofilament heavy, middle and light chains (NF-H, NF-M and NF-L). Neurofilaments assemble and form through the association of their central alpha-helical coiled-coil rod domains. NF-H and NF-M are distinct from NF-L as they contain a carboxyl-terminal tail domain, which appears to form connections with adjacent structures and other neurofilaments. Together with other axonal components such as microtubules, they form the dynamic axonal cytoskeleton. They maintain and regulate neuronal cytoskeletal plasticity through the regulation of neurite outgrowth, axonal caliber and axonal transport. Neurofilaments contain KSP repeats that are consensus motifs for the proline-directed kinases and are extensively phosphorylated in vivo, and their functions are thought to be regulated through their phosphorylation. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed kinase, whose activity is restricted to the neuron through the neuronal-specific distribution of its activators p35 and p39. Cdk5 is the only kinase that affects the electrophoretic mobility of human NF-H and is thought to be the major neurofilament kinase. Cdk5 is involved in crosstalk with other signal transduction pathways such as the mitogen-activated protein kinase and myelin-associated glycoprotein pathways to influence the phosphorylation of neurofilaments and other cytoskeletal proteins. Both the hyperactivation of Cdk5 activity and subsequent hyperphosphorylation of neurofilaments and the microtubule-associated protein tau have been implicated in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis. Here we review the functions of neurofilaments and the significance of Cdk5 phosphorylation of neurofilaments.
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PMID:Cyclin-dependent kinase 5 in neurofilament function and regulation. 1467 12

Inflammation is a process that has been actively related with the onset of several neurodegenerative disorders including Alzheimer disease (AD). However, the precise implications of inflammatory response for neurodegeneration have not been elucidated. A current hypothesis considers that extracellular insults to neurons could trigger the production of inflammatory cytokines by astrocytes and microglia. These cytokines, namely, interleukin (IL)-1beta, TNFalpha, and IL-6, could affect the normal behavior of neuronal cells. In the present study, we describe the effect of the administration at physiologic doses of one of these cytokines, IL-6, to hippocampal neurons, on the protein kinase pathways as well as on the tau phosphorylation patterns. IL-6-treated neurons exhibited an increase in the amount of anomalously hyperphosphorylated tau protein in epitopes dependent on proline-directed protein kinases (PDPKs). On the basis of our data, the observed increase of tau epitopes of Alzheimer type is explained by an increase of intraneuronal levels of p35 activator and in the activity of the protein kinase cdk5 in response to this cytokine. Further confirmation of cdk5 involvement in this process was based on the findings that inhibition of the kinase activity with butyrolactone-I prevents the appearance of tau of Alzheimer type in IL-6-treated neurons. Additional studies suggest that an increase of cdk5 activity could be mediated by a known signaling cascade described for IL-6 function, namely, the MAPK-p38 signaling pathway. Stimulation of the IL-6 pathway appears to increase the tau epitopes of Alzheimer type, as demonstrated in studies with specific inhibitors. These results support the findings of a pathologic role for IL-6 in the neuroinflammatory response as related with the pathogenesis of neuronal degeneration.
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PMID:Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. 1505 7

Microtubule-associated protein tau in a hyperphosphorylated state is the major component of the filamentous lesions that define a number of neurodegenerative diseases commonly referred to as tauopathies. Hyperphosphorylation of tau at most sites appears to precede filament assembly. Many of the hyperphosphorylated sites are serine/threonine-proline sequences. Here we show that c-Jun N-terminal kinases JNK1, JNK2 and JNK3 phosphorylate tau at many serine/threonine-prolines, as assessed by the generation of the epitopes of phosphorylation-dependent anti-tau antibodies. Of the three protein kinases, JNK2 phosphorylated the most sites in tau, followed by JNK3 and JNK1. Phosphorylation by JNK isoforms resulted in a greatly reduced ability of tau to promote microtubule assembly. These findings extend the number of candidate protein kinases for the hyperphosphorylation of tau in Alzheimer's disease and other neurodegenerative disorders.
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PMID:Phosphorylation of microtubule-associated protein tau by isoforms of c-Jun N-terminal kinase (JNK). 1522 92

The peptidyl-prolyl cis-trans isomerase (PPIase) Pin1 modulates the activity of a range of target proteins involved in the cell cycle, transcription, translation, endocytosis, and apoptosis by facilitating dephosphorylation of phosphorylated serine or threonine residue preceding a proline (p-Ser/Thr-Pro) motifs catalyzed by phosphatases specific for the trans conformations. Pin1 targets include the neuronal microtubule-associated protein tau, whose dephosphorylation restores its ability to stabilize microtubules. We, and others, have shown that tau hyperphosphorylation in the neurofibrillary tangles (NFTs) of Alzheimer disease (AD) is associated with redirection of the predominantly nuclear Pin1 to the cytoplasm and with Pin1 shortfalls throughout subcellular compartments. As nuclear Pin1 depletion causes apoptosis, shortfalls in regard to both nuclear and p-tau targets may contribute to neuronal dysfunction. We report here that similar Pin1 redistribution and shortfalls occur in frontotemporal dementias (FTDs) characterized by abnormal protein aggregates of tau and other cytoskeletal proteins. This may be a unifying, contributory factor towards neuronal death in these dementias.
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PMID:Shortfalls in the peptidyl-prolyl cis-trans isomerase protein Pin1 in neurons are associated with frontotemporal dementias. 1547 61

A double transgenic mouse expressing the amyloid precursor protein, bearing the Swedish mutations, and expressing tau protein containing three of the mutations present in frontotemporal dementia linked to chromosome 17 (FTDP-17), has been characterized. In the double transgenic mouse an increase in tau phosphorylation at serine S262 and S422 was observed compared with that found in simple transgenic mice. The phosphorylation at S262 was also found, in a much lower level, in the single transgenic mouse expressing amyloid precursor protein (APP), and it was absent in that overexpressing tau variant. Additionally, in the double transgenic mouse a slight increase in the amount of sarkosyl insoluble tau polymers was observed in comparison with that found in single transgenic tau mouse. Also, wider tau filaments were found in the double transgenic mouse compared with those found in the single transgenic mouse. Our results suggest that beta-amyloid peptide could facilitate the phosphorylation of tau at a site not directed by proline, such as serine 262, and that modification could facilitate tau aberrant aggregation. Also, they suggest that different types of tau filamentous polymers can occur in different mouse models for tauopathies, like those used for Alzheimer's disease or FTDP-17.
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PMID:Characterization of a double (amyloid precursor protein-tau) transgenic: tau phosphorylation and aggregation. 1566 90

Alzheimer's disease (AD) is three times more prevalent in women than men, and epidemiological studies have shown that estrogen replacement in aging women forestalls the onset of AD. Hyperphosphorylation of the tau protein that forms the neurofibrillary tangles found in AD brains might be responsible for the breakdown of microtubules in affected neurons. The mechanisms by which tau protein is phosphorylated in the AD brain are not fully understood. Using a human neuroblastoma cell line (SH-SY5Y) and primary cultures of newborn male or female rat cerebral cortical neurons, we investigated the effect of 17beta-estradiol on tau protein expression and phosphorylation. We found that estradiol increased total tau and induced dephosphorylation at the proline-directed site of the molecule. Further, estradiol prevented okadaic acid-induced hyperphosphorylation of tau in both proline- and non-proline-directed sites, and antiestrogens blocked this effect. To our knowledge, this is the first report of an effect of estradiol on naturally occurring and induced tau phosphorylation. This assumes special significance because the estrogen action was found to be sexually dimorphic in rat cortical neurons and differentiation-sensitive in human neuroblastoma cells.
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PMID:Estradiol prevents neural tau hyperphosphorylation characteristic of Alzheimer's disease. 1602 64


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