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 Alzheimer-like state of tau protein includes phosphorylation by a proline-directed Ser/Thr kinase present in normal or pathological human brain. Extending earlier results on MAP kinase, we show here that the proline-directed kinase, GSK3, can induce an Alzheimer-like immune response involving several distinct and phosphorylatable epitopes at Ser-Pro motifs, as well as a gel mobility shift, similar to MAP kinase. Both kinases behave like microtubule-associated proteins in that they co-purify through cycles of assembly and disassembly, and both kinases are directly associated with paired helical filaments.
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PMID:Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. 133 49

Glycogen synthase kinase-3 (GSK-3) reduced the mobility of human tau on SDS-PAGE, prevented binding of the monoclonal antibody (mAb), Tau.1, and induced binding of the mAb 8D8. Recombinant tau phosphorylated by GSK-3 aligned on SDS-PAGE with the abnormally phosphorylated tau (PHF-tau) associated with the paired helical filaments in Alzheimer's disease brain. Phosphorylated serine396 (numbering of the largest human brain tau isoform) was identified as a binding site on tau for mAb 8D8. The localisation of GSK-3 within granular structures in pyramidal cells indicates that GSK-3 alpha and GSK-3 beta may have a role in the production of PHF-tau in Alzheimer's disease.
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PMID:Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. 133 52

tau protein kinase I (TPKI) purified from bovine brain extract has been shown to phosphorylate tau and to form paired helical filament (PHF) epitopes and was found recently to be identical to glycogen synthase kinase -3 beta (GSK-3 beta). Before elucidating a role of TPKI/GSK-3 beta in PHF formation, it is necessary to investigate the normal function of the enzyme. To study the distribution and developmental changes of the enzyme, specific polyclonal antibodies were prepared against TPKI and GSK-3 alpha. Immunoblot analysis demonstrated that TPKI was nearly specifically localized in the brain of adult rats. The level of TPKI in the rat brain was high at gestational day 18, peaked on postnatal day 8, and then decreased rapidly to a low level, which was sustained up to 2 years. Immunohistochemistry indicated primarily neuronal localization of TPKI. Growing axons were stained most intensely in the developing cerebellum, but the immunoreactivity became restricted to the gray matter in the mature tissue. Parallel fibers had a high level of TPKI and also stained intensely for tau. These findings indicate that tau is one of the physiological substrates of TPKI and suggest that the enzyme plays an important role in the growth of axons during development of the brain.
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PMID:Localization and developmental changes of tau protein kinase I/glycogen synthase kinase-3 beta in rat brain. 751 46

Proline-directed kinases such as the mitogen-activated protein (MAP) kinases, cyclin-dependent protein kinase 5 (CDK5) and glycogen synthase 3 (GSK3) have been implicated in the hyperphosphorylation of the tau protein associated with Alzheimer's disease. Such aberrant phosphorylation of tau appears to compromise on its ability to bind to and stabilize microtubules, and this may contribute to Alzheimer's disease pathology. In this review, the architecture of the intracellular signal transduction pathways that regulate proline-directed kinases is described. The MAP kinases serve as major intersection points in the flow of information from a plethora of extracellular stimuli and affect diverse cellular processes that are often important for cell proliferation. Although brain contains terminally differentiated neurons, many of the known components of MAP kinase-dependent lines of communication are highly expressed in the nervous system. Similar signalling pathways may also regulate CDK5 and GSK3. In mitotic cells, abnormal activation of the protein kinase network at multiple points can contribute to oncogenic transformation. It is proposed that Alzheimer's disease may also result from accumulated defects in the kinase network that governs the proline-directed kinases such that their inappropriate activation is sustained in the affected neurons. A detailed understanding of proline-directed kinase-dependent pathways may permit the identification of rational targets for the therapeutic intervention of Alzheimer's disease and other neurological disorders.
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PMID:Networking with proline-directed protein kinases implicated in tau phosphorylation. 756 35

We previously reported that tau protein kinase I (TPKI) induced normal tau protein into a state of paired helical filaments (PHF); this is further confirmed here by immunoblot analysis using several antibodies. We also present the amino acid sequence of TPKI, which is identical to glycogen synthase kinase 3 beta (GSK3 beta). Moreover, we found that TPKI activity was inseparable from GSK3 activity throughout the purification procedure. These results indicate that TPKI is identical to GSK3 beta.
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PMID:Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. 768 8

Previously, tau protein kinase I/glycogen synthase kinase-3 beta/kinase FA(TPKI/GSK-3 beta/FA) was identified as a brain microtubule-associated tau kinase possibly involved in the Alzheimer disease-like phosphorylation of tau. In this report, we find that the TPKI/GSK-3 beta/FA can be stimulated to phosphorylate brain tau up to 8.5 mol of phosphates per mol of protein by heparin, a polyanion compound. Tryptic digestion of 32P-labeled tau followed by high-performance liquid chromatography and high-voltage electrophoresis/thin-layer chromatography reveals 12 phosphopeptides. Phosphoamino acid analysis together with sequential manual Edman degradation and peptide sequence analysis further reveals that TPKI/GSK-3 beta/FA after heparin potentiation phosphorylates tau on sites of Ser199, Thr231, Ser235, Ser262, Ser396, and Ser400, which are potential sites abnormally phosphorylated in Alzheimer tau and potent sites responsible for reducing microtubule binding possibly involved in neuronal degeneration. The results provide initial evidence that TPKI/GSK-3 beta/FA after heparin potentiation may represent one of the most potent systems possibly involved in the abnormal phosphorylation of PHF-tau and neuronal degeneration in Alzheimer disease brains.
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PMID:Tau protein kinase I/GSK-3 beta/kinase FA in heparin phosphorylates tau on Ser199, Thr231, Ser235, Ser262, Ser369, and Ser400 sites phosphorylated in Alzheimer disease brain. 778 11

Extensive in vitro phosphorylation of a purified preparation of control human brain tau consistently produces four rather than, as previously believed, three tau species on SDS-PAGE. The species thus generated are shifted on SDS-PAGE to positions that match those of PHF-tau isolated from Alzheimer's disease brain. A mixture of recombinant human tau isoforms phosphorylated by GSK-3 beta gave similar results to those obtained with control human brain tau. In vitro phosphorylation of the individual recombinant isoforms by GSK-3 beta showed that the four bands of PHF-tau are likely to consist of isoforms 3R,0 alone; 4R,0 with 3R,29; 4R,29 with 3R,58 and 4R,58 alone.
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PMID:PHF-tau from Alzheimer's brain comprises four species on SDS-PAGE which can be mimicked by in vitro phosphorylation of human brain tau by glycogen synthase kinase-3 beta. 805 May 97

We examined the subcellular distribution of two glycogen synthase kinase-3 (GSK-3) isoforms in rat cerebellum. Results from immunoelectron microscopy and subcellular fractionation revealed that one isoform, tau protein kinase I/GSK-3 beta (TPKI/GSK-3 beta), was present in mitochondria, but GSK-3 alpha was not. Although the two GSK-3 isoforms seem to have similar properties, the difference of subcellular localization observed here suggests that TPKI/GSK-3 beta fulfills some specific function in mitochondria.
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PMID:Different localization of tau protein kinase I/glycogen synthase kinase-3 beta from glycogen synthase kinase-3 alpha in cerebellum mitochondria. 857 78

Exposure of rat hippocampal neurons to the peptide amyloid beta (A beta) (25-35) as well as A beta (1-40) peptides enhances phosphorylation of tau to a paired helical filament (PHF)-state through activation of tau protein kinase I (TPK I)/glycogen synthase kinase-3 beta (GSK-3 beta) [Busciglio, J., Lorenzo, A., Yeh, J. and Yankner, B.A., Neuron, 14 (1995) 879-888; Takashima, A., Ishiguro, K., Noguchi, K., Michel, G., Hoshi, M., Sato, K., Takahashi, M., Hoshino, T., Uchida, T. and Imahori, K., Neurosci. Meeting Abstr., 671 (1995) 17]. In order to examine the effects of A beta treatment on intracellular signaling mechanism, we have investigated the role of phosphatidyl inositol-3 (PI-3) kinase in the phosphorylation of tau. A beta (25-35) exposure induced an inactivation of PI-3 kinase and an activation of TPK I/GSK-3 beta in rat hippocampal culture. Wortmannin, an inhibitor of PI-3 kinase, also activated TPK I/GSK-3 beta, leading to an enhancement of tau phosphorylation and neuronal death in hippocampal culture. These results suggest that A beta (25-35) inhibition of PI-3 kinase results in the activation of TPK I/GSK-3 beta, the phosphorylation of tau, and resultant neuronal death in rat hippocampal neurons.
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PMID:Exposure of rat hippocampal neurons to amyloid beta peptide (25-35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3 beta. 874 40

Previously, we determined sites of tau protein phosphorylation by tau protein kinase (TPK) I/glycogen synthase kinase 3 beta (GSK-3 beta) and TPKII/(cyclin-dependent kinase 5 (CDK5) + p23). We prepared antibodies specific for these sites of tau phosphorylated by TPKI and TPKII, using chemically synthesized phosphopeptides as antigens. Each antibody specifically reacts with each phosphorylation site. With these antibodies, it was confirmed that TPKI and TPKII are responsible for these phosphorylation sites, as reported previously, except that Ser404 is also weakly phosphorylated by TPKI alone. It was also observed that TPKII-phosphorylation enhances TPKI-phosphorylation. These results indicate that these antibodies are useful tools for investigation of the phosphorylation of tau by TPKI and TPKII.
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PMID:Analysis of phosphorylation of tau with antibodies specific for phosphorylation sites. 878 36


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