UNIPROT:P10636 - FACTA Search

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

Phosphorylation of tau protein at Ser-262 has been shown to diminish its ability to bind to taxol-stabilized microtubules. The paired helical filaments (PHFs) found in Alzheimer's disease brain are composed of PHF-tau, which is hyperphosphorylated at multiple sites including Ser-262. However, protein kinase(s) able to phosphorylate this site are still under investigation. In this study, the ability of cyclic AMP-dependent protein kinase (cAMP-PK) and calcium/calmodulin-dependent protein kinase II (CaMKII) to phosphorylate tau at Ser-262, as well as Ser-356, is demonstrated by use of a monoclonal antibody (12E8) which has been shown to recognize tau when these sites are phosphorylated. Cleavage of cAMP-PK-phosphorylated tau at cysteine residues by 2-nitro-5-thiocyanobenzoic acid, which cuts the protein into essentially two fragments and separates Ser-262 from Ser-356, revealed that cAMP-PK phosphorylates both Ser-262 and Ser-356. In addition, phosphorylation with cAMP-PK or CaMKII of recombinant tau in which Ser-262, Ser-356 or both had been mutated to alanines, clearly demonstrated that cAMP-PK and CaMKII were able to phosphorylate both sites. Mitogen-activated protein kinase or protein kinase C did not phosphorylate tau at Ser-262 and/or Ser-356. Finally, evidence is presented that phosphorylation of both these sites occurs in cultured nerve cells under certain conditions, indicating their potential physiological relevance.
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PMID:Tau protein is phosphorylated by cyclic AMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II within its microtubule-binding domains at Ser-262 and Ser-356. 868 13

The microtubule-associated protein tau of normal brains is attached to tubulin through its 18-amino-acid repeat units. In the paired helical filaments (PHF) of Alzheimer's disease, however, tau is oligomerized in an abnormally hyperphosphorylated from (PHF-tau). tau contains two cysteine residues in repeat units 2 and 3, but only the R3-R3 homodimer is present in PHF-tau. A serine residue two amino acids downstream of the R3 cysteine is a major phosphate acceptor site for protein kinase C. In the work repeated here, we used synthetic peptides corresponding to R2, R3 and phosphorylated R3 to determine the binding of the tau repeat peptides to a peptide fragment corresponding to the C-terminal domain of beta-tubulin and to study the kinetics of homo- and heterodimer formation. Additionally, we studied two major biochemical properties of the peptides that distinguish between normal tau and PHF-tau: conformation and metabolic stability. All R2 and R3 peptides bound specifically to the tubulin peptide regardless of the state of phosphorylation or dimerization. The reverse-turn conformation of the tau repeat peptides in the presence of the tubulin peptide remained unaffected. Phosphorylation slightly loosened the turn structure of the monomeric and dimeric peptides, and did not univocally affect the serum stability of the peptides or the ability of the peptides to form dimers. The isolated R2 and R3 units formed homodimers approximately in the same rate. When the two peptides were mixed, however, the R2-R3 heterodimer was formed preferentially over the homodimers. The dimers were generally more stable in human serum than the monomers. Our results with the synthetic peptide fragments of tau indicate that neither oxidation nor phosphorylation of the repeat units is able to generate extended structure such as that found in PHF-tau. Additionally, phosphorylation of Ser324 does not appear to modulate the kinetics of oligomerization of tau, and in general biochemistry terms, does not affect disulfide bridge formation nearby. In agreement with studies at the full-protein level, the formation of homodimers of the peptides, a model of the self-association of tau, is not preferred. If the dimers are formed, however, their clearance is considerably slower than that of the monomers, explaining the remarkable protease resistance of PHF-tau in the affected brains.
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PMID:Oxidized and phosphorylated synthetic peptides corresponding to the second and third tubulin-binding repeats of the tau protein reveal structural features of paired helical filament assembly. 927 97

Phorbol esters such as 12-O-tetradeonyl phorbol-13 acetate (TPA) induce a time-dependent biphasic effect on protein kinase C (PKC)-mediated events by fostering translocation of cytosolic (latent) PKC to the plasma membrane (where it is activated). Continued treatment, however, depletes the cell's entire PKC complement and induces a functional stake of PKC inhibition. Previous studies from several laboratories have demonstrated that long-term TPA treatment, like treatment with PKC inhibitors, induces neuronal differentiation. Bryostatin-1 also induces translocation and overall downregulation of PKC following long-term treatment, yet, unlike TPA or PKC inhibitors, does not induce neuronal differentiation, promoting controversy regarding the role of PKC inhibition in neuronal differentiation. We demonstrate herein that, despite overall downregulation in human neuroblastoma cells, membrane-associated levels of one PKC isoform (PKC epsilon) are actually increased following long-term bryostatin-1 treatment. Since previous studies have implicated this PKC isoform in phosphorylation of the microtubule-associated protein tau and in neuritogenesis, we examined the consequences of long-term bryostatin treatment on these phenomena. Treatment with 25 n-100 M bryostatin-1 for 72 h increased tau phosphorylation and inhibited neuritogenesis. By contrast, treatment with either TPA or the PKC inhibitor staurosporine did not induce tau phosphorylation and induced neurite elaboration. Bryostatin-1 antagonized neurite induction by staurosporine. These findings provide additional evidence for a unique role of PKC epsilon in the regulation of tau phosphorylation and neuronal differentiation, and demonstrate that bryostatin-1 can function under certain conditions as a selective PKC epsilon activator even following long-term treatment.
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PMID:Selective activation by bryostatin-1 demonstrates unique roles for PKC epsilon in neurite extension and tau phosphorylation. 956 34

Attempts to describe a mechanism of neurofibrillary tangle formation often focus on site specific phosphorylations of tau protein. These have typically been described in both Alzheimer's disease and developing brains. Therefore, study of the developmental regulation of Alzheimer epitope tau phosphorylations may help explain their persistence or recurrence during Alzheimer's disease. Using fetal rat hippocampal cultures, we report a spatial and temporal expression of tau phosphorylation during neuronal differentiation. We have examined phosphorylation at the epitopes recognized by monoclonal antibodies, PHF-1 and Tau 1. Tau was highly phosphorylated at the PHF-1 epitope at all culture ages examined using both immunohistochemical staining and Western blots. Tau was heavily phosphorylated at the Tau 1 epitope only in older cultures. The populations of tau recognized by the two antibodies also exhibited different solubilities, suggesting different microtubule binding behaviors: tau phosphorylated at PHF-1 was retained in axons following solubilization whereas Tau 1 immunoreactive tau was not retained in any cell compartment. Finally, in this culture system, maintenance of phosphorylation at the PHF-1 epitope, but not the Tau 1 epitope, required protein kinase C activity. These results indicate unique regulatory mechanisms and roles for each of these phosphorylated tau epitopes.
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PMID:Developmental regulation and PKC dependence of Alzheimer's-type tau phosphorylations in cultured fetal rat hippocampal neurons. 960

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

Glutamate receptor induced changes in the activity of different phosphorylation systems were measured in hippocampal slices from 12- and 56-day-old rats, by determining the endogenous phosphorylation of 2.5% perchloric acid (PCA) soluble proteins. We identified among these proteins an 85, 80 kDa and the tau protein as specific substrates for protein kinase A (PKA), MARCKS, and neurogranin as specific substrates for protein kinase C (PKC), and prostaglandin-D-synthase as substrate for casein kinase II (CKII). In addition, a 35 kDa protein was phosphorylated by calcium/calmodulin dependent kinase II and protein kinase C and a 21 kDa protein was a substrate for all investigated kinases. The basal endogenous phosphorylation of 2.5% PCA soluble proteins changed during development qualitatively and quantitatively. Thus, the phosphorylation degree of nearly all proteins declines during maturation. Activation of mGluR induced an increased phosphorylation of PKA, PKC, and CKII substrates in hippocampal slices from 12-day-old rats, but in slices of 56-day-old rats only PKA and to a lower extent PKC substrates were affected. In contrast, stimulation of NMDA receptors led to an enhancement of CKII and PKA dependent phosphorylation only in slices of young animals, whereas the endogenous phosphorylation of some proteins in adult slices was actually decreased. These data showing developmental changes in the coupling of metabotropic and ionotropic glutamate receptors to different phosphorylation systems are discussed in the light of altered physiological properties of the mature hippocampus.
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PMID:Age-dependent differences in glutamate-induced phosphorylation systems in rat hippocampal slices. 1022 77

The role of the phosphatidylinositol-3 kinase pathway in the hyperphosphorylation of tau protein was investigated in cultured cells. Human kidney 293T-cells were cotransfected with tau and glycogen synthase kinase-3 (GSK-3) genes or tau and protein kinase B genes. The phosphorylation of tau protein was increased by cotransfection with GSK-3; however, it was decreased by cotransfection with protein kinase B. Human neuroblastoma SY5Y cells were treated with wortmannin, an inhibitor of phosphatidylinositol-3 kinase, and only transient (after 1 hour) activation of GSK-3 and hyperphosphorylation of tau protein were observed. However, continuous inactivation of protein kinase B was observed, suggesting the involvement of protein kinases other than protein kinase B in the phosphorylation and inactivation of GSK-3 after 3 hours. In cells treated with wortmannin, protein kinase C delta fragments were observed, and the protein kinase C activity increased after 3 hours, whereas treatment of cells with z-DEVD-fmk, an inhibitor of caspase-3, inhibited fragmentation of protein kinase C delta and induced continuous activation of GSK-3. It is suggested that fragmentation of protein kinase C delta during the process of apoptosis results in the phosphorylation and the inactivation of GSK-3. Those data suggest that, in Alzheimer disease, more complicated mechanisms are involved in the process of phosphorylation of tau protein predominantly regulated by P13K pathway.
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PMID:Significance of tau phosphorylation and protein kinase regulation in the pathogenesis of Alzheimer disease. 1085 Jul 26

We analyzed the effects of PKNalpha and protein kinase C (PKC) on phosphorylation of tau protein by glycogen synthase kinase (GSK)-3beta using monoclonal antibodies (AT8, AT180, and AT270). These antibodies are highly specific for phosphorylated tau in Alzheimer paired helical filaments, and recognize phosphorylated Ser202/Thr205, Thr231, and Thr181 of tau protein, respectively. Immunoblot analysis demonstrated that PKNalpha and PKC did not directly phosphorylate their sites, whereas GSK-3beta efficiently did so. Incubating GSK-3beta with PKNalpha or PKC subtypes inhibited subsequent GSK-3beta-induced AT8 and AT270 immunoreactivity. However, the constitutive active form of the GSK-3beta(S9A) mutant was almost totally inert to each enzyme. Incubating tau with PKNalpha increased the GSK-3beta-induced AT180 immunoreactivity, which was further enhanced when the S9A mutant was used instead of the wild type GSK-3beta. These results suggest that PKNalpha and PKC directly inhibit GSK-3beta activity at least in part by phosphorylating Ser9 of GSK-3beta, and that they indirectly suppress GSK-3beta-stimulated phosphorylation of tau at amino acids Ser202/Thr205 and Thr181, but enhanced phosphorylation at Thr231 through phosphorylation at other sites of tau.
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PMID:Dual effects of PKNalpha and protein kinase C on phosphorylation of tau protein by glycogen synthase kinase-3beta. 1087 88

Mitogen-activated protein kinases (such as Erk1/2) regulate phosphorylation of the microtubule-associated protein tau and processing of the amyloid protein beta, both events critical to the pathophysiology of Alzheimer's disease (AD). Here we report that enhanced and prolonged Erk1/2 phosphorylation in response to bradykinin (BK) was detected in fibroblasts of both familial and sporadic AD, but not age-matched controls (AC). The AD-associated abnormality in Erk1/2 phosphorylation was not seen in fibroblasts from Huntington's disease patients with dementia. The elevation of Erk1/2 phosphorylation occurred immediately after BK stimulation and required an IP3-sensitive Ca(2+) release as well as activation of PKC and c-src as upstream events. Treatment of cells with the PI-3 kinase blocker LY924002 partially inhibited the BK-stimulated Erk1/2 phosphorylation in AC, but had no effect in AD cells, suggesting that the BK-induced Erk1/2 phosphorylation in AD cells is independent of PI-3 kinase. Activation of the cAMP-responsive element binding protein (CREB) monitored as an increase in phosphorylation at Ser-133 was also observed after BK stimulation. Unlike the AD-specific differences for Erk1/2, however, the BK-stimulated CREB phosphorylation was not different between AC and AD cells. Abnormal Erk1/2 activities may alter downstream cellular processes such as gene transcription, amyloid precursor protein processing, and tau protein phosphorylation, which contribute to the pathogenesis of AD. Moreover, detection of AD-specific differences in MAP kinase in peripheral tissues may provide an efficient means for early diagnosis of AD as well as help us to identify therapeutic targets for drug discovery.
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PMID:MAP kinase signaling cascade dysfunction specific to Alzheimer's disease in fibroblasts. 1246 May 56

Glycogen synthase kinase-3beta (GSK-3beta) is implicated in regulating apoptosis and tau protein hyperphosphorylation in Alzheimer's disease (AD). We investigated the effects of two key AD molecules, namely apoE (E3 and E4 isoforms) and beta-amyloid (Abeta) 1-42 on GSK-3beta and its major upstream regulators, intracellular calcium and protein kinases C and B (PKC and PKB) in human SH-SY5Y neuroblastoma cells. ApoE3 induced a mild, transient, Ca2+-independent and early activation of GSK-3beta. ApoE4 effects were biphasic, with an early strong GSK-3beta activation that was partially dependent on extracellular Ca2+, followed by a GSK-3beta inactivation. ApoE4 also activated PKC-alpha and PKB possibly giving the subsequent GSK-3beta inhibition. Abeta(1-42) effects were also biphasic with a strong activation dependent partially on extracellular Ca2+ followed by an inactivation. Abeta(1-42) induced an early and potent activation of PKC-alpha and a late decrease of PKB activity. ApoE4 and Abeta(1-42) were more toxic than apoE3 as shown by MTT reduction assays and generation of activated caspase-3. ApoE4 and Abeta(1-42)-induced early activation of GSK-3beta could lead to apoptosis and tau hyperphosphorylation. A late inhibition of GSK-3beta through activation of upstream kinases likely compensates the effects of apoE4 and Abeta(1-42) on GSK-3beta, the unbalanced regulation of which may contribute to AD pathology.
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PMID:Apolipoprotein E and beta-amyloid (1-42) regulation of glycogen synthase kinase-3beta. 1462 95

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