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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The paired helical filament (PHF), which comprises the major fibrous element of the neurofibrillary tangle of Alzheimer's disease, is composed of abnormally phosphorylated microtubule-associated protein tau. Here we show that p42 MAP kinase phosphorylates recombinant tau and converts it to a form which is similar to PHF tau. Of the major serine/threonine protein phosphatases found in mammalian tissues only protein phosphatase 2A (PP2A) could dephosphorylate tau phosphorylated in this manner, with PP2A1 being the most effective form of the enzyme.
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PMID:p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer's disease [corrected]. 133 Jun 87

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

The microtubule-associated protein tau is a major component of the paired helical filaments (PHFs) observed in Alzheimer's disease brains. The pathological tau is distinguished from normal tau by its state of phosphorylation, higher apparent M(r) and reaction with certain antibodies. However, the protein kinase(s) have not been characterized so far. Here we describe a protein kinase from brain which specifically induces the Alzheimer-like state in tau protein. The 42 kDa protein belongs to the family of mitogen activated protein kinases (MAPKs) and is activated by tyrosine phosphorylation. It is capable of phosphorylating Ser-Pro and Thr-Pro motifs in tau protein (approximately 14-16 P1 per tau molecule). By contrast, other proline directed Ser/Thr kinases such as p34(cdc2) combined with cyclin A or B have only minor effects on tau phosphorylation. We propose that MAP kinase is abnormally active in Alzheimer brain tissue, or that the corresponding phosphatases are abnormally passive, due to a breakdown of the normal regulatory mechanisms.
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PMID:Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. 137 45

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 have previously demonstrated that the secreted form of the beta-amyloid precursor protein (beta-APP) activates mitogen-activated protein (MAP) kinases in PC-12 pheochromocytoma cells. beta-APP as well as other treatments that activate MAP kinase also enhance phosphorylation of the microtubule-associated protein tau in these cells. In this study, we extended this analysis to neurons. Using dissociated cultures of cortical neurons, we found that exposure to beta-APP activated MAP kinase 4 and 7 days but not 1 day after plating. Phosphorylation of tau in neurons was measured by immunoreactivity with the AT8 antibody, which recognizes a phosphorylated epitope present in tau from paired helical filaments. We found that activation of MAP kinase in neurons was associated with increased amounts of AT8-reactive tau. These results support a role for MAP kinase in transducing the biological effects of secreted beta-APP on neurons and suggest possible mechanisms by which beta-APP might be involved in the pathogenesis of Alzheimer's disease.
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PMID:Secreted beta-APP stimulates MAP kinase and phosphorylation of tau in neurons. 756 49

Abnormally phosphorylated tau protein is a major component of the cytoskeletal pathology of Alzheimer's disease (AD) found in the neurofibrillary tangle (NFT) and neuritic plaque (NP). Identification of the kinase responsible for this phosphorylation has been difficult. In the test tube, several proline-directed kinases, particularly mitogen-activated protein (MAP) and cdc2 kinase, phosphorylate tau on sites that appear to mimic the abnormally phosphorylated sites in AD. Important unanswered issues include: 1) whether this phosphorylation event occurs in the tightly regulated environment of a living cell; 2) whether this phosphorylation of tau affects its functional properties; and 3) what is the subcellular relationship of proline-directed kinases and tau. We show here that tau can be phosphorylated in cultured hippocampal neurons by the MAP kinase p44mpk, and phosphorylation of tau compromises its functional ability to assemble microtubules. We show further that MAP kinase copurifies with microtubule fractions where it is tyrosine phosphorylated and presumably active. These studies address and raise several important issues regarding the regulation of tau phosphorylation in normal and AD brain.
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PMID:p44mpk MAP kinase induces Alzheimer type alterations in tau function and in primary hippocampal neurons. 768 58

Microtubule-associated protein tau is abnormally hyperphosphorylated in the brain of patients with Alzheimer disease (AD). Previous studies have shown (i) that in vitro tau can be phosphorylated to an Alzheimer abnormally phosphorylated state-like protein by proline-directed protein kinases MAP kinase and p34cdc2, and (ii) that the AD abnormally phosphorylated tau can be in vitro dephosphorylated by protein phosphatases PP-2B, PP-2A and PP-1 and not by PP-2C. However, to have a direct effect on the regulation of phosphorylation of tau, these enzymes should be present in the affected neurons. In the present study immunocytochemical localization of protein phosphatases PP-1, PP-2A, PP-2B and PTP, and protein kinases MAP kinase and p34cdc2 were studied in the hippocampal formation of AD and as a control in non-demented elderly patients. All the protein phosphatases and protein kinases studied were localized to both granular and pyramidal neurons. In the pyramidal neurons, the enzymes staining was observed in neuronal soma and neurites. PTP-1B, PP-1 and PP-2A were also highly expressed in microglia. The topographical distributions of all the enzymes studied were similar, i.e. the intensity of immunostaining in hippocampus in end-plate (CA3 and CA4) > prosubiculum, subiculum > entorhinal cortex > dentate gyrus > CA2 > CA1. Furthermore, the expression of all the enzymes was also observed in the tangle-bearing neurons. The PP-2B staining of the tangle-bearing neurons was weaker than the unaffected neurons in the same tissue section field in AD cases.
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PMID:Expression of protein phosphatases (PP-1, PP-2A, PP-2B and PTP-1B) and protein kinases (MAP kinase and P34cdc2) in the hippocampus of patients with Alzheimer disease and normal aged individuals. 781 92

Microtubule-associated protein tau from Alzheimer brain has been shown to be phosphorylated at several ser/thr-pro and ser/thr-X sites (Hasegawa, M. et al., J. Biol. Chem. 267, 17047-17054, 1992). Several proline-dependent protein kinases (PDPKs) (MAP kinase, cdc2 kinase, glycogen synthase kinase-3, tubulin-activated protein kinase, and 40 kDa neurofilament kinase) are implicated in the phosphorylation of the ser-thr-pro sites. The identity of the kinase(s) that phosphorylate the ser/thr-X sites are unknown. To identify the latter kinase(s) we have compared the phosphorylation of bovine tau by several brain protein kinases. Stoichiometric phosphorylation of tau was achieved by casein kinase-1, calmodulin-dependent protein kinase II, Gr kinase, protein kinase C and cyclic AMP-dependent protein kinase, but not with casein kinase-2 or phosphorylase kinase. Casein kinase-1 and calmodulin-dependent protein kinase II were the best tau kinases, with greater than 4 mol and 3 mol 32P incorporated, respectively, into each mol of tau. With the sequential addition of these two kinases, 32P incorporation approached 6 mol. Peptide mapping revealed that the different kinases largely phosphorylate different sites on tau. After phosphorylation by casein kinase-1, calmodulin-dependent protein kinase II, Gr kinase, cyclic AMP-dependent protein kinase and casein kinase-2, the mobility of tau isoforms as detected by SDS-PAGE was decreased. Protein kinase C phosphorylation did not produce such a mobility shift. Our results suggest that one or more of the kinases studied here may participate in the hyperphosphorylation of tau in Alzheimer disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of the phosphorylation of microtubule-associated protein tau by non-proline dependent protein kinases. 803 84

We have shown earlier that certain proline-directed kinases such as MAP kinase or GSK-3 can phosphorylate tau protein in an abnormal manner reminiscent of tau from Alzheimer paired helical filaments [Drewes et al. (1992); Mandelkow et al. (1992)]. Both kinases are abundant in brain tissue and associate physically with microtubules through several cycles of assembly and disassembly. In this report we show that cdk2/cyclin A incorporates = 5 Pi into recombinant tau, and that it also induces the MR shift and antibody reactivity typical of Alzheimer tau. However, since there is no cdk2 in brain [Meyerson et al. (1992)] we looked for other members of this family of kinases. Using an antibody against the conserved N-terminus we isolated a cdk-like kinase from brain which was capable of inducing the Alzheimer-like characteristics in tau by phosphorylation. Its size (31 kDa), target specificity (proline-directed), chromatographic behavior, and abundance in brain suggest that this kinase is similar or identical to the neuronal cdc2-like kinase nclk alias PSSARLE or cdk5 [Hellmich et al. (1992); Meyerson et al. (1992); Xiong et al. (1992); Tsai et al. (1993)]. This was confirmed by an antibody specific for cdk5. Like MAP kinase and GSK-3, this kinase is physically associated with microtubules and can be enriched by cycles of microtubule assembly and disassembly. Thus, cdk5 should be regarded as another kinase that could be held responsible for the changes in tau protein during Alzheimer disease progression.
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PMID:Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. 828 4

We have shown previously that brain tissue contains protein kinases which can phosphorylate tau protein to a state reminiscent of the pathological state of Alzheimer paired helical filaments (PHFs); these include proline-directed kinases which phosphorylate SP or TP motifs (such as MAP kinase and GSK-3) [Drewes et al. (1992); Mandelkow et al. (1992)], as well as a novel kinase which phosphorylates S262 of tau protein and thereby strongly reduces the binding of tau to microtubules [Biernat et al. (1993)]. Here we report on the corresponding phosphatases in brain which normally keep the 'pathological' sites free of phosphate. The major phosphatases acting on tau are calcineurin and PP-2A, but not PP-1. Both are present and active in brain extracts, they can dephosphorylate recombinant tau after prior phosphorylation with either MAP kinase, GSK-3, or brain extract, and the course of dephosphorylation can be monitored with antibodies diagnostic of the pathological state of tau. Both phosphatases also act directly on PHF tau isolated from Alzheimer brains.
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PMID:Dephosphorylation of tau protein and Alzheimer paired helical filaments by calcineurin and phosphatase-2A. 828 5


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