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)

Cyclin-dependent kinase 5 (CDK5) is the 34 kDa catalytic subunit of a recently characterized neuronal cdc2-like protein kinase which appears to be involved in regulation of the neurocytoskeleton. Using the rat postdecapitative model, the effect of brain ischemia on histone H1 and tau protein CDK5 phosphorylating activity was examined. Histone H1 kinase activity increased in both cytosolic and particulate fractions of the hippocampus and neocortex after 5 min and 15 min of ischemia, then declined to control levels. CDK5 tau protein phosphorylating activity increased after 15 min ischemia; however, no electrophoretic shifts or changes in radiodensity of the tau bands were observed autoradiographically. On Western blot analysis, the CDK5 protein band did not change after 25 min ischemia, despite the increase and subsequent decline in enzyme activity. These data demonstrate a postischemic increase in CDK5 activity, an associated increase in CDK5 tau phosphorylating activity and a decline in activity in the absence of massive proteolysis. CDK5 appears to play a role in the events associated with neuronal response to ischemic injury.
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PMID:Cyclin-dependent protein kinase 5 activity increases in rat brain following ischemia. 930 12

In Alzheimer's disease, the microtubule-associated protein tau forms paired helical filaments (PHFs) that are the major structural component of neurofibrillary tangles. Although tau isolated from PHFs (PHF-tau) is abnormally phosphorylated, the role of this abnormal phosphorylation in PHF assembly is not known. Previously, neuronal cdc2-like protein kinase (NCLK) was shown to phosphorylate tau on sites that are abnormally phosphorylated in PHF-tau (Paudel, H. K., Lew, J., Ali, Z., and Wang, J. H. (1993) J. Biol. Chem. 268, 23512-23518). In this study, phosphorylation by NCLK was found to promote dimerization of recombinant human tau (R-tau) and brain tau (B-tau) purified from brain extract. Chemical cross-linking by disuccinimidyl suberate (DSS), a homobifunctional chemical cross-linker that specifically cross-linked R-tau dimers, and a Superose 12 gel filtration chromatography revealed that R-tau preparations contain mixtures of monomeric and dimeric R-tau species. When the structure of NCLK-phosphorylated R-tau was studied by a similar approach, DSS preferentially cross-linked the phosphorylated R-tau over the nonphosphorylated R-tau, and the phosphorylated R-tau eluted as a dimeric species from the gel filtration column. Phosphorylated R-tau became resistant to DSS upon dephosphorylation and was recovered as a monomeric species from the gel filtration column. In the presence of a low concentration of dithiothreitol (1.65 microM), R-tau formed disulfide cross-linked R-tau dimers. When compared, phosphorylated R-tau formed more disulfide cross-linked dimers than the nonphosphorylated R-tau. B-tau also was specifically cross-linked to dimers by DSS. When B-tau and NCLK-phosphorylated B-tau were treated with DSS, phosphorylated B-tau was preferentially cross-linked over nonphosphorylated counterpart. Taken together, these results suggest that phosphorylation by NCLK promotes dimerization and formation of disulfide cross-linked tau dimers, which is suggested to be the key step leading to PHF assembly (Schweers, O., Mandelkow, E.-M., Biernat, J., and Mandelkow, E. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 8463-8467).
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PMID:Phosphorylation by neuronal cdc2-like protein kinase promotes dimerization of Tau protein in vitro. 935 89

This study examined the phosphorylation of tau on Ser 262, within the first microtubule-binding domain, by a developmentally regulated 100 kDa protein kinase exhibiting significantly greater activity in the embryonic rat brain than in the adult rat brain. This protein kinase co-purified with microtubules and co-immunoprecipitated with both tau and MAP-2. In addition to phosphorylating tau, MAP-2, and a Ser 262-containing peptide, the present protein kinase activity was shown to autophosphorylate as determined by the in-gel kinase assay in the absence of any protein or peptide polymerized into the matrix. Phosphorylation of tau with this protein kinase significantly reduced the tau-microtubule interaction, and the effect was significantly greater with microtubule-associated protein (MAP) preparations from embryonic brain than with preparations from the adult. Ser 262 is phosphorylated extensively in paired helical filament (PHF) tau from Alzheimer's disease (AD) brain, to a lesser extent in fetal tau, and only to a very minor extent in biopsy-derived human tau. Because the 100 kDa protein kinase activity phosphorylates Ser 262 and is higher in the fetal brain than the adult brain, it is hypothesized that an inappropriate re-expression and/or re-activation of this or a similar developmentally regulated protein kinase could contribute to the phosphorylation of Ser 262 in PHF-tau, and thus play a role in the pathogenesis of AD.
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PMID:Phosphorylation of microtubule-associated protein tau on Ser 262 by an embryonic 100 kDa protein kinase. 936 62

The protein kinase activity tightly associated with paired helical filaments (PHFs) purified from the brain tissue of individuals with Alzheimer's disease has been characterized in vitro. The activity is shown to phosphorylate casein, an exogenous substrate, with a maximal velocity of approximately 2 nmol/min/mg, suggesting it comprises a significant component of the total protein in the PHF preparation. On the basis of substrate selectivity, isoquinoline sulfonamide inhibitor selectivity, in-gel renaturation assays, and western analysis, the activity consists of closely related members of the alpha branch of the casein kinase 1 family of protein kinases. Because of its tight association with PHFs and its phosphate-directed substrate selectivity, casein kinase 1 is positioned to participate in the pathological hyperphosphorylation of tau protein that is observed in neurodegenerative diseases such as Alzheimer's disease.
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PMID:Casein kinase 1 is tightly associated with paired-helical filaments isolated from Alzheimer's disease brain. 937 84

Families bearing mutations in the presenilin 1 (PS1) gene develop Alzheimer's disease. Previous studies have shown that the Alzheimer-associated mutations in PS1 increase production of amyloid beta protein (Abeta1-42). We now show that PS1 also regulates phosphorylation of the microtubule-associated protein tau. PS1 directly binds tau and a tau kinase, glycogen synthase kinase 3beta (GSK-3beta). Deletion studies show that both tau and GSK-3beta bind to the same region of PS1, residues 250-298, whereas the binding domain on tau is the microtubule-binding repeat region. The ability of PS1 to bring tau and GSK-3beta into close proximity suggests that PS1 may regulate the interaction of tau with GSK-3beta. Mutations in PS1 that cause Alzheimer's disease increase the ability of PS1 to bind GSK-3beta and, correspondingly, increase its tau-directed kinase activity. We propose that the increased association of GSK-3beta with mutant PS1 leads to increased phosphorylation of tau.
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PMID:Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. 968 33

Epithelial cells play an important role in maintaining the intestinal mucosa barrier, a barrier that is impaired in several inflammatory conditions. The mechanisms behind this impairment are not known, but it can be presumed that structural alterations of the epithelial cells are involved. In support of this notion, we here show the inflammatory mediator leukotriene D4 (LTD4) triggered first a rapid (10 s) increase and immediately thereafter (30 s) a sustained decrease in the cellular filamentous actin (F-actin) level in intestinal epithelial cells. The initial LTD4-induced increase in F-actin content was effectively blocked by preincubating the cells with either pertussis toxin or the tyrosine kinase inhibitor genistein. A possible involvement of the tyrosine kinase-dependent phosphatidylinositol-3-kinase (PI-3-kinase) in the polymerisation of actin was supported by the observations that LTD4 induced a translocation to a membrane fraction of PI-3-kinase and by the findings that wortmannin, a PI-3-kinase inhibitor, totally abolished both this translocation of PI-3-kinase as well as the initial LTD4-induced polymerisation of actin. In addition, pertussis toxin and genistein, both known to interfere with the LTD4-induced calcium signal, completely or partially reversed the actin-depolymerising effect of LTD4. The calcium ionophore ionomycin (30s) induced actin depolymerisation to the same extent as LTD4 (30 s) did, but lacked the initial effect on actin polymerisation. In cells loaded with the calcium chelator MAPT, LTD4 induced a normal actin polymerisation response but the subsequent depolymerisation was completely inhibited. Similar results were obtained when the cells were preincubated with the protein kinase A inhibitor Rp-cAMPS, which has been shown to impair the LTD4-induced calcium signal in these epithelial cells. The present results show that the inflammatory mediator LTD4 triggers a reorganisation of the actin network in intestinal epithelial cells that is likely to contribute to the impairment of the intestinal barrier function.
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PMID:The inflammatory mediator leukotriene D4 triggers a rapid reorganisation of the actin cytoskeleton in human intestinal epithelial cells. 971 65

The paired helical filaments (PHFs) found in Alzheimer's disease (AD) brains are composed primarily of the microtubule-associated protein tau. PHF-tau is in a hyperphosphorylated state and is unable to promote microtubule assembly. We investigated whether the inhibition of tau binding to microtubules is increased when tau is phosphorylated by different kinases in combination with GSK-3. We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II. From these observations we estimate that the phosphorylation of Thr 231, Ser 235, and Ser 262 contributes approximately 26, approximately 9, and approximately 33%, respectively, of the overall inhibition of tau binding to microtubules. Together, our results indicate that the binding of tau to microtubules is controlled by the phosphorylation of several sites, among which are Thr 231, Ser 235, and Ser 262.
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PMID:Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. 973 71

A possible role for a protein kinase, PKN, a fatty acid-activated serine/threonine kinase with a catalytic domain homologous to the protein kinase C family and a direct target for Rho, was investigated in the pathology of Alzheimer's disease (AD) using a sensitive immunocytochemistry on postmortem human brain tissues and a kinase assay for human tau protein. The present study provides evidences by light, electron, and confocal laser microscopy that in control human brains, PKN is enriched in neurons, where the kinase is concentrated in a subset of endoplasmic reticulum (ER) and ER-derived vesicles localized to the apical compartment of juxtanuclear cytoplasm, as well as late endosomes, multivesicular bodies, Golgi bodies, secretary vesicles, and nuclei. In AD-affected neurons, PKN was redistributed to the cortical cytoplasm and neurites and was closely associated with neurofibrillary tangles (NFTs) and their major constituent, abnormally modified tau. PKN was also found in degenerative neurites within senile plaques. In addition, we report that human tau protein is directly phosphorylated by PKN both in vitro and in vivo. Thus, our results suggest a specific role for PKN in NFT formation and neurodegeneration in AD damaged neurons.
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PMID:A protein kinase, PKN, accumulates in Alzheimer neurofibrillary tangles and associated endoplasmic reticulum-derived vesicles and phosphorylates tau protein. 973 60

Several kinases have been shown to phosphorylate tau protein at Ser-262, an important site involved in the regulation of the binding of tau to microtubules. In this study we compared the phosphorylation of tau at Ser-262 by CaMKII, PhK and PKA in vitro as determined by radioimmunoblots developed by the monoclonal antibody 12E8 which recognizes P-Ser-262 and P-Ser-356; and Ab-262, a polyclonal antibody which is specific to unphosphorylated Ser-262 in tau. We found that the phosphorylation at Ser-262 was several times more effective by CaMKII than PKA or PhK. Employing rat brain extract as a source of all brain kinases and KN-62, a specific inhibitor of CaMKII, we found that CaMKII accounts for approximately 45% of phosphorylation at Ser-262. Furthermore, in rat brain slices kept metabolically active in oxygenated artificial CSF, phosphorylation of tau at Ser-262 was (i) increased up to 120% in the presence of bradykinin, a CaMKII activator, and (ii) inhibited by approximately 35% in the presence of KN-62. Thus, CaMKII is a major tau Ser-262 kinase in mammalian brain.
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PMID:Ser-262 in human recombinant tau protein is a markedly more favorable site for phosphorylation by CaMKII than PKA or PhK. 980 Nov 71

According to the amyloid hypothesis for the pathogenesis of Alzheimer's disease (AD), amyloid beta peptide (Abeta) directly affects neurons, leading to neurodegeneration and tau phosphorylation, followed by the production of paired helical filaments (PHF) in neurofibrillary tangles (NFT). To analyze the relationship between the phosphorylation sites of tau and the activation of kinases in response to Abeta, we treated cultured rat hippocampal neurons with a peptide fragment of Abeta, Abeta(25-35). Abeta(25-35) treatment activated tau protein kinase I/glycogen synthase kinase-3beta (TPKI/GSK-3beta) but not glycogen synthase kinase-3alpha (GSK-3alpha) or mitogen activated protein kinase (MAP kinase) in primary culture of hippocampal neurons. Using antibodies that recognize phosphorylated sites of tau, we showed that tau phosphorylation was enhanced in at least five sites (Ser199, Ser202, Ser396, Ser404, and Ser413 numbered according to the human tau isoform containing 441 amino acid residues), to an extent that depended on the level of TPK I/GSK-3beta. Treatment with TPK I/GSK-3beta antisense oligonucleotide inhibited the enhancement of tau phosphorylation induced by Abeta(25-35) exposure. Thus, TPK I/GSK-3beta activation by Abeta(25-35) may lead to extensive tau phosphorylation.
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PMID:Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons. 980 90


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