Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 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

Many of the extracellular signals such as neurotransmitters and hormones regulate the intracellular concentration of second messengers such as cAMP, cGMP, and calcium ion (Ca2+), diacylglycerol and IP3. Accumulating evidence indicates that protein phosphorylation-dephosphorylation is an important mechanism by which second messengers act to regulate a variety of cellular processes. Ca2+/calmodulin-dependent protein kinase II, cAMP-dependent protein kinase and protein kinase C are three major classes of protein kinases in the central nervous system. In an attempt to elucidate the physiological roles of the protein kinases, I have been studying the substrate proteins and functional significance of the enzymes and phosphorylated proteins. For these purposes, I investigated the phosphorylation-dephosphorylation of cytoskeletal proteins such as microtubule-associated protein 2 and tau, which are involved in the assembly-disassembly of microtubules and the production of abnormally phosphorylated forms of tau in neurofibrillary tangles in Alzheimer's disease brain. As the natural consequence, studying the protein phosphatases is significant for elucidating the switch-off mechanism of protein phosphorylation. Thus, I have been investigating the functional significance of protein phosphorylation-dephosphorylation for the elucidation of signal transduction in the brain, which is widely involved in the regulation of brain functions.
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PMID:[Molecular and pharmacological studies on signal transduction in the brain]. 872 Feb 94

This paper presents a comprehensive survey of the pathogenesis and pathophysiology of Alzheimer's disease (AD). Two mechanisms are of etiological importance in the development of a degenerative dementing brain disease: 1. Lesions in the mitochondrial genome that are caused by free radicals. Primary degenerative AD is characterized by a tendency to acquire random lesions within mitochondrial DNA that are produced by free radicals. The consequence of these lesions is a decrease in glucose turnover and a decline in oxidative phosphorylation. Point mutations on chromosome 21 are hypothesized to increase the susceptibility of mitochondrial DNA to lesions created by free radicals. 2. Ischemic brain lesions as well as traumatic brain damage cause an increase in the release of excitotoxic amino acids (glutamate, aspartate, etc.). These neurotransmitters increase CA(+2) influx into the nerve cell and significantly lower energy production. From a pathogenetic point of view, AD is characterized by a decrease in glucose turnover in the brain. The progression of AD can be monitored by F18- deoxyglucose PET studies. This technique also allows the recognition of patients who are prone to develop AD. The actual development of a cognitive deficit is a threshold phenomenon that occurs if glucose turnover in the hippocampus or temporoparietal cortex drops below a critical level of about 40% of the level of age-matched controls. The low glucose turnover in AD causes a cholinergic deficit by decreasing the synthesis of AcCoA, which is used by choline acetyltransferase in the acetylation of choline to acetylcholine. The decrease in glucose turnover also reduces oxidative phosphorylation. The resulting decrease in ATP triggers the hyperphosphorylation of tau protein by activating protein kinase 40erk. The hyperphosphorylation leads to the development of paired helical filaments. The generation of beta amyloid and the loss of neuronal synapses are also caused by a decrease in oxidative phosphorylation, since beta amyloid precursor proteins are not inserted into the membranes of nerve cells in the absence of a sufficient amount of ATP. This results in the generation of intact beta amyloid molecules and leads to amyloidosis in the brains of patients with Alzheimer's disease.
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PMID:The significance of glucose turnover in the brain in the pathogenetic mechanisms of Alzheimer's disease. 873 75

Amyloid beta protein (A beta) is deposited characteristically in the brain of patients with Alzheimer's disease. Effects of protein kinase inhibitors (H-89, H-7, KN-62) on A beta-induced neuronal cell death were examined in primary culture of dissociated cerebral cortical cells. beta(25-35), the active fragment of A beta, induced neuronal cell death with apoptotic features including chromatin condensation and DNA fragmentation. The cell death was attenuated by cycloheximide or by H-89, a specific protein kinase A (PKA) inhibitor, but not by H-7 or KN-62. These data suggest that beta(25-35) induces apoptotic cell death through the PKA-mediated pathway.
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PMID:Protein kinase inhibitor attenuates apoptotic cell death induced by amyloid beta protein in culture of the rat cerebral cortex. 874 21

Transgenic mice expressing the oncogenic protein-serine/threonine kinase Mos at high levels in the brain display progressive neuronal degeneration and gliosis. Gliosis developed in parallel with the onset of postnatal transgene expression and led to a dramatic increase in the number of astrocytes positive for GFAP, vimentin, and possibly tau. Interestingly, vimentin is normally expressed only in immature or neoplastic astrocytes, but appears to be induced to high levels in Mos-transgenic, mature astrocytes. Mos can activate mitogen activated protein kinase (MAPK) and MAPK has been implicated in Alzheimer-type tau phosphorylation. In the Mos-transgenic brain we found increased levels of phosphorylation at one epitope on tau containing serines 199 and 202 (numbering according to human tau), a pattern similar but not identical to that found in Alzheimer's disease. In addition, Mos-transgenic mice express a novel neurofilament-related protein that might be a proteolytic neurofilament heavy chain degradation product. These results suggest that activation of protein phosphorylation in neurons can result in changes in cytoskeletal proteins that might contribute to neuronal degeneration.
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PMID:Neurodegenerative changes including altered tau phosphorylation and neurofilament immunoreactivity in mice transgenic for the serine/threonine kinase Mos. 874 4

The purpose of this study was to compare the effects of aging and Alzheimer disease (AD) on the important intracellular signaling enzyme cAMP-dependent protein kinase A (PKA) in cerebral microvessels. PKA activity and levels were measured in microvessels isolated from the brains of adult and aged rodents as well as from the cerebral cortices of AD and elderly control patients. The results showed that cerebral microvessels from aged rats have significantly (p < 0.01) higher PKA activity and levels when compared to cerebral microvessels from adult rats. In contrast, no significant difference was found between PKA activity or levels in cerebral microvessels from AD patients when compared to controls. These results indicate that in cerebral microvessels both PKA activity and levels increase with age but are unaffected by AD. The data suggest that protein phosphorylation in brain microvessels may be affected differentially by aging and dementia.
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PMID:cAMP-dependent protein kinase in cerebral microvessels in aging and Alzheimer disease. 874 27

Protein phosphorylation induced by neurotransmitters, hormones, different growth factors, nerve impulse is involved in the regulation of a wide variety of physiological processes in the nervous system. The data on abnormal phosphorylation/dephosphorylation processes in the brain of patients with Alzheimer's disease are considered. In AD there are a few phosphoproteins with known function, protein kinases, phosphatases that are altered. The own data on the decrease in casein kinase 2 activity, content and altered spectrum of substrate proteins in Alzheimer's disease are presented. Drastic reductions in zinc- and magnesium-stimulated protein tyrosine activities are also recorded. The important role of abnormalities in the phosphorylation/dephosphorylation system in the stimulation of pathological processes in Alzheimer's disease is noted.
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PMID:[Protein phosphorylation in the normal nervous system and in Alzheimer's disease]. 875 73

Antibody Ab262 was raised against a synthetic tau peptide (SKIGSTENLK, amino acids 258-267 of tau, termed Ser262 peptide). The antibody was more reactive with Ser262 peptide and unphosphorylated tau than a related phosphopeptide [SKIGS(P)TENLK, termed PSer262 peptide] and tau phosphorylated by a partially purified kinase, glycogen synthase kinase (GSK) 3 beta. AB262 reacted poorly with a peptide having the sequence DRV-QSKIGSLD (amino acids 348-358). Treatment of PSer262 peptide or GSK 3 beta phosphorylated tau with alkaline phosphatase increased Ab262 immunoreactivity, indicating that Ab262 is a reagent useful for studying tau phosphorylation at the Ser262 residue. The Ab262 immunoreactivity was detected in tau from normal brains and Alzheimer paired helical filament (PHF-tau) and in PHFs. Alkaline phosphatase treatment had no effect on the Ab262 immunoreactivity of normal tau and PHF-tau but altered the tau-1 and PHF-1 immunoreactivities, tau proteins from rat brains at 3 and 8 h postmortem exhibited 5 and 19%, respectively, more Ab262 immunoreactivity than tau from fresh tissues. In comparison, rat tau at 8 h postmortem was 40% more immunoreactive with Tau-1. The results suggest that Ser262 is not a major phosphorylation site in vivo. Moreover, there is little or no difference between PHF-tau and normal tau in the extent of phosphorylation at Ser262.
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PMID:The state of phosphorylation of normal adult brain tau, fetal tau, and tau from Alzheimer paired helical filaments at amino acid residue Ser262. 876 76

A monoclonal antibody (AP422) specific for phosphoserine 422 in microtubule-associated protein tau has been produced. It strongly labels paired helical filament (PHF) tau from Alzheimer's disease brain in a phosphorylation-dependent manner. By contrast, AP422 only labels a small fraction of fetal tau and a very small fraction of tau from adult brain. The amount of tau phosphorylated at Ser-422 in normal brain is minor relative to that phosphorylated at sites recognized by other phosphorylation-dependent anti-tau antibodies of known epitope. It follows that AP422 is the most specific anti-tau antibody available for detecting the neurofibrillary lesions of Alzheimer's disease. We also show that Ser-422 in tau is a good in vitro substrate for mitogen-activated protein kinase, but not for glycogen synthase kinase-3 or neuronal cdc2-like kinase.
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PMID:Characterization of mAb AP422, a novel phosphorylation-dependent monoclonal antibody against tau protein. 879 96

The phosphorylation state of tau changes during neurodevelopment and highly phosphorylated tau accumulates in the paired helical filaments found in Alzheimer's disease. In non-neuronal mammalian cells transiently expressed tau is predominantly not phosphorylated at sites known to be phosphorylated in paired helical filaments. However this pattern of phosphorylation is induced by both glycogen synthase kinase-3 alpha and -3 beta and here we show that this results in a change in the intracellular properties of tau. Within cells tau is bound to cytoskeletal structures and causes changes in cellular cytoarchitecture with the induction of thick and stable microtubule bundles. This morphology is lost when tau is co-expressed with glycogen synthase kinase-3 beta; microtubules become less stable and are not bound by tau. Independently of any direct or indirect effects on tau, glycogen synthase kinase-3 beta induces some but relatively slight changes in microtubule organization with the loss of a prominent centrosomal microtubular origin. The cytoskeleton is critical to cell function and within post-mitotic neurons has a highly specialized structure induced, in part, by the neuronal-specific microtubule-associated proteins such as tau. In vitro studies have suggested that the properties of tau are regulated by phosphorylation as highly phosphorylated tau does not promote tubulin polymer assembly. We have demonstrated, in intact cells, that tau highly phosphorylated in the presence of glycogen synthase kinase-3 beta loses the properties of microtubule binding and stabilization, suggesting that regulation of tau phosphorylation by this enzyme might be an important mechanism whereby cytoskeletal function is modulated during neurodevelopment and lost in neurodegeneration.
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PMID:Phosphorylation of tau by glycogen synthase kinase-3 beta in intact mammalian cells: the effects on the organization and stability of microtubules. 880 31


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