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)

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

When a synthetic peptide fragment (VAVVRTPPKSPSSAK) which corresponds to amino acid residues 226-240 from brain microtubule-associated protein tau was used as a testing substrate, we found that protein kinase FA/GSK-3 alpha was almost inactive towards this substrate. In sharp contrast, when Ser-10 of this peptide was replaced by a phosphoserine, the phosphopeptide fragment (VAVVRTPPKS(p)PSSAK) became an excellent substrate for kinase FA/GSK-3 alpha. Sequential manual Edman degradation together with phosphoamino acid analysis and protein sequencing further revealed that Thr-6 of the peptide fragment which corresponds to an important abnormal phosphorylation site Thr-231 in Alzheimer's diseased brain tau was the only site that was greatly phosphorylated, demonstrating that a pre-phosphorylation becomes a prerequisite and is essential for promoting phosphorylation of Thr-231. Taken together, the results provide initial evidence that kinase FA/GSK-3 alpha mediates a synergistic phosphorylation control mechanism involved in the abnormal site phosphorylation of Alzheimer's diseased brain tau.
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PMID:Synergistic control mechanism for abnormal site phosphorylation of Alzheimer's diseased brain tau by kinase FA/GSK-3 alpha. 750 67

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

Tau protein, the major component of the aberrant structures termed paired helical filaments (PHFs) present in the brain of Alzheimer's disease patients, is pathologically phosphorylated in sites in and around the tubulin-binding sites. A single protein kinase, glycogen synthase kinase 3 (GSK 3), is able to phosphorylate tau at the flanking regions and, additionally, at the tubulin-binding motifs if heparin or tubulin is present. Serines-262 and -324 have been found to be modified at the tubulin-binding region of tau protein by GSK 3 in the presence of heparin or tubulin.
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PMID:Glycogen synthase kinase 3 phosphorylates recombinant human tau protein at serine-262 in the presence of heparin (or tubulin). 755 45

Abundant neurofibrillary tangles, neuropil threads and senile plaque neurites constitute the neurofibrillary pathology of Alzheimer's disease. They form in the nerve cells that undergo degeneration in the disease, in which their regional distribution correlates with the degree of dementia. Each lesion contains the paired helical filament (PHF) as its major fibrous component. Recent work has shown that PHFs are composed of the microtubule-associated protein tau in a hyperphosphorylated state. PHF-tau is hyperphosphorylated on six adult brain tau isoforms. As a consequence, tau is unable to bind to microtubules and is believed to self-assemble into the PHF. Current evidence suggests that protein kinases or protein phosphatases with a specificity for serine/threonine-proline residues are instrumental in the hyperphosphorylation of tau. Candidate protein kinases include mitogen-activated protein kinase, glycogen synthase kinase 3 and cyclin-dependent kinase 5, whereas the trimeric form of protein phosphatase 2A is a candidate phosphatase.
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PMID:Molecular dissection of the neurofibrillary lesions of Alzheimer's disease. 776 34

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

Pyramidal neurons in affected regions of Alzheimer's disease (AD) brain contain neurofibrillary tangles (NFT), aggregates of paired helical filaments (PHF) composed mainly of phosphorylated microtubule-associated protein tau. To explore the role of tau phosphorylation in the aggregation of tau into PHF, we constructed mammalian cell culture systems producing high levels of intracellular phosphorylated tau. COS-1 fibroblast-like cells were transiently transfected to simultaneously express tau, MAP kinase (MAPK), and MAP kinase kinase (MAPKK), or alternatively to express tau and glycogen synthase kinase 3 (GSK3). B103 neuron-like cells (which contain MAPK but little tau or GSK3) were stably transfected to express tau or tau and GSK3. In both systems, GSK3-transfected cells contained tau AT8/M (defined by AT8 staining and tau PHF-like mobility), but MAPK-transfected cells required phosphatase inhibitors, such as okadaic acid (OKA) or calyculin (CAL), to produce tau AT8/M. In vitro, the same concentrations of CAL and OKA inhibit phosphatases 1 and 2A (PP1 and PP2A), except that 100-1000 times as much OKA is needed to inhibit PP1. Inducing tau phosphorylation at the AT8 site in MAPK-transfected cells required 2-10 times more OKA than CAL, suggesting both PP1 and PP2A helped block the phosphorylation. Though levels of tau AT8/M reached 2-8% of total cellular proteins in COS-1 cells, the ratio of particulate to supernatant tau levels did not increase, and no tangles were observed; perhaps post-translational modifications or co-aggregating proteins are needed to induce PHF.
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PMID:Overexpressed tau protein in cultured cells is phosphorylated without formation of PHF: implication of phosphoprotein phosphatase involvement. 875 Aug 56

Using immunohistochemistry, we examined the localization of four types of proline-directed kinases in the brains of control rats and in the brains of non-demented aged human subjects, subjects with Alzheimer's disease and those with Down's syndrome. The four kinases were: cyclin-dependent kinase (cdk) 5, a component of tau protein kinase (TPK) II; TPK I/glycogen synthase kinase (GSK)-3 beta; GSK-3 alpha; and mitogen-activated protein kinase (MAPK/ERK2). Each of these kinases has been reported to promote the hyperphosphorylation of tau protein in vitro. The kinases were located essentially in neurons, although the intensity and distribution of labeling varied. Antiserum for cdk5 showed the most preferential and consistent labeling of intraneuronal neurofibrillary tangles (NFT). Antiserum for TPK I/GSK-3 beta also labeled intraneuronal NFT. Double immunolabeling for TPK I/GSK-3 beta and tau 1 showed that TPK I/GSK-3 beta was closely associated with NFT. Antiserum for GSK-3 alpha labeled neurons weakly, and the intensity of labeling did not differ between neurons with and without NFT. Antiserum for MAPK labeled neurons in superficial cortical layers, but NFT appeared in both superficial and deep cortical layers. These findings suggest that cdk5 and TPK I/GSK-3 beta are the critically important kinases for the generation in vivo of hyperphosphorylated tau, the main component of the paired helical filaments in NFT.
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PMID:Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II. 887 Aug 24

Several peptides derived from microtubule-associated tau protein, have been tested as substrates for glycogen synthase kinase 3 (GSK 3). In the absence of cofactors, GSK 3 can modify serines or threonines followed by prolines. In other cases, a phosphorylation in position +4 is required for the phosphorylation of threonine/serine residues. A third type of substrate can be modified by GSK 3 in the presence of heparin. The comparison of GSK 3 with other kinases suggests some similar features of this kinase with proline-directed protein kinases, such as cdc-2 or mitogen-activated protein kinase (MAP Kinases,) and also with casein kinase 2 (CK 2). Thus, all these kinases are specifically inhibited by 5,6-Dichloro-1-(beta-D-ribofuranosyl)-benzimidazole (DRB). However, heparin is an inhibitor of CK 2 whereas it activates the modification of certain substrates by GSK 3. A possible explanation for the obtained results is that the consensus sequence for GSK 3 phosphorylation is a serine/threonine adjacent to a proline or other beta-turn former residue and that such recognition could be favoured by the presence of adjacent negative charges or the addition of polyanions.
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PMID:Glycogen synthase kinase 3 phosphorylation of different residues in the presence of different factors: analysis on tau protein. 897 80

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


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