Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abundant neurofibrillary tangles, neuropil threads and plaque neurites constitute the neurofibrillary pathology of Alzheimer's disease. They form in the nerve cells that undergo degeneration in the disease where 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 play an important role 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 paired helical filament. 756 42

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

Mammalian neurofilament proteins, particularly midsized (NF-M) and heavy (NF-H) molecular weight neurofilament proteins, are highly phosphorylated in axons. Neurofilament function depends on the state of phosphorylation of the numerous serine/threonine residues in these proteins. Most phosphorylation occurs in the lys-ser-pro (KSP) repeats in the C-terminal tail domains of NF-H and NF-M. In our previous study, cyclin-dependent kinase 5 (cdk5) was shown to phosphorylate specifically the KSPXK repeats in rat NF-H. Because 80% of the repeats are of the KSPXXXK type, it was of interest to determine which kinase phosphorylates these motifs. Using a synthetic KSPXXXK peptide to screen for a specific kinase, we fractionated rat brain extracts by column chromatography and identified extracellular signal-regulated kinase (Erk2) activated by an upstream activator, the mitogen-activated protein kinase kinase MAPKK (MEK), by Western blot analysis, sequence identification, and inhibition by a specific MEK inhibitor (PD 98059). The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. A comparative kinetic study of Erk2 and cdk5 phosphorylation of KSPXK and KSPXXXK peptides revealed that, in contrast to cdk5, which phosphorylated only the KSPXK peptide, Erk2 could phosphorylate both. The preferred substrate for Erk2 was KSPXXXK peptide. The MEK inhibitor PD 98059 also inhibited phosphorylation of NF-H, NF-M, and microtubule-associated protein (MAP) in primary rat hippocampal cells and caused a decrease in neurite outgrowth, suggesting that Erk1,2 may play an important role in neurite growth and branching. These data suggest that neuronal Erk1 and Erk2 are capable of phosphorylating serine residues in diverse KSP repeat motifs in NF-M and NF-H.
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PMID:Mitogen-activated protein kinases (Erk1,2) phosphorylate Lys-Ser-Pro (KSP) repeats in neurofilament proteins NF-H and NF-M. 959 82

Glial cytoplasmic inclusions (GCI) characteristically occur in the oligodendrocytes of patients with multiple system atrophy (MSA). However, the molecular mechanisms underlying GCI formation are unknown. To investigate whether these inclusions are related to proline-directed protein kinases that have been associated with neuronal inclusion bodies in some other neurodegenerative diseases, we immunohistochemically probed tissue samples from MSA brains with a panel of antibodies against cyclin-dependent kinases and mitogen-activated protein kinase. We unexpectedly detected cyclin-dependent kinase 5- (cdk5) and mitogen-activated protein kinase- (MAPK) immunoreactivities in GCI. We also found TAU1 immunoreactivity in GCI, and a strong expression of microtubule-associated protein (MAP) 2 immunoreactivity in oligodendrocytes of MSA brains. This immunoreactivity was not observed in the normal or neurological controls. The accumulated evidence suggest a close association between GCI and the microtubular cytoskeleton. Cdk5 phosphorylates tau and MAP2, and MAPK is capable of phosphorylating MAP2. The present results suggest that the aberrant or ectopic expression of cdk5 and MAPK causes abnormal phosphorylation of microtubular cytoskeletal proteins, thus leading to GCI formation in affected oligodendrocytes.
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PMID:Cyclin-dependent kinase 5 and mitogen-activated protein kinase in glial cytoplasmic inclusions in multiple system atrophy. 969 Jun 73

This article reviews current knowledge of neurofilament structure, phosphorylation, and function and neurofilament involvement in disease. Neurofilaments are obligate heteropolymers requiring the NF-L subunit together with either the NF-M or the NF-H subunit for polymer formation. Neurofilaments are very dynamic structures; they contain phosphorylation sites for a large number of protein kinases, including protein kinase A (PKA), protein kinase C (PKC), cyclin-dependent kinase 5 (Cdk5), extracellular signal regulated kinase (ERK), glycogen synthase kinase-3 (GSK-3), and stress-activated protein kinase gamma (SAPK gamma). Most of the neurofilament phosphorylation sites, located in tail regions of NF-M and NF-H, consist of the repeat sequence motif, Lys-Ser-Pro (KSP). In addition to the well-established role of neurofilaments in the control of axon caliber, there is growing evidence based on transgenic mouse studies that neurofilaments can affect the dynamics and perhaps the function of other cytoskeletal elements, such as microtubules and actin filaments. Perturbations in phosphorylation or in metabolism of neurofilaments are frequently observed in neurodegenerative diseases. A down-regulation of mRNA encoding neurofilament proteins and the presence of neurofilament deposits are common features of human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease. Although the extent to which neurofilament abnormalities contribute to pathogenesis in these human diseases remains unknown, emerging evidence, based primarily on transgenic mouse studies and on the discovery of deletion mutations in the NF-H gene of some ALS eases, suggests that disorganized neurofilaments can provoke selective degeneration and death of neurons. An interference of axonal transport by disorganized neurofilaments has been proposed as one possible mechanism of neurofilament-induced pathology. Other factors that can potentially lead to the accumulation of neurofilaments will be discussed as well as the emerging evidence for neurofilaments as being possible targets of oxidative damage by mutations in the superoxide dismutase enzyme (SOD1); such mutations are responsible for approximately 20% of familial ALS cases.
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PMID:Neurofilaments in health and disease. 975 17

Phosphorylation of the neurofilament-H subunit (NF-H) was investigated in rat embryonic brain neurons in culture. A portion of the NF-H was phosphorylated in vivo at embryonic day 17 when brain neurons were prepared. When the neurons were isolated and cultured, the NF proteins disappeared once and then reappeared over the next several days in the following order: (1) NF-L/NF-M, (2) dephosphorylated NF-H and (3) phosphorylated NF-H. Phosphorylation of NF-H began around 4 days after cell plating, at about the time of synapse formation. Treatments that appeared to modulate the timing of synapse formation also affected the timing of NF-H phosphorylation: (1) earlier phosphorylation was observed at higher neuronal cell density, (2) earlier phosphorylation was observed in neurons cultured on a coating substrate that promotes rapid neurite extension and (3) phosphorylation was suppressed when neurite extension was inhibited by brefeldin A. Three possible synapse formation-induced events, excitation, cell-cell contact through adhesion proteins and elevated concentrations of neurotrophic factors, were examined for their possible involvement in generating the signal for NF-H phosphorylation. Neither excitation nor cell contact enhanced NF-H phosphorylation. Neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) stimulated phosphorylation of NF-H. The BDNF-stimulated phosphorylation was inhibited by an anti-BDNF antibody and K252a, an inhibitor of BDNF receptor TrkB tyrosine kinase. Among known NF-H kinases of cyclin-dependent kinase 5 (CDK5), external signal-regulated protein kinase (ERK) and stress-activated protein kinase (SAPK), CDK5 and SAPK showed an increase in kinase activity or an active form with a time course similar to NF-H phosphorylation in control culture. On the other hand, BDNF stimulated the kinase activity of CDK5 and induced appearance of an active form of ERK transiently. These results suggest a possibility that synapse formation induces NF-H phosphorylation, at least in part, through activation of CDK5 by BDNF.
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PMID:Brain-derived neurotrophic factor-induced phosphorylation of neurofilament-H subunit in primary cultures of embryo rat cortical neurons. 1068 53

To examine the role of c-Jun N-terminal kinase (JNK/SAPK) in the developing nervous system of vertebrates, the localization of an active form of JNK, phosphorylated JNK (p-JNK), was studied in the lumbosacral spinal cord of the chick embryo. We also examined the localization of phosphorylated neurofilaments (NFs, potential targets of p-JNK) and cyclin-dependent kinase 5 (Cdk5), which is known to phosphorylate cytoskeletal proteins, including NFs, and compared their expression with that of p-JNK. Additionally, the localization of phosphorylated forms of c-Jun and ATF-2 was compared with that of p-JNK. On embryonic day 3 (E3), the expression of p-JNK was observed in regions containing early-projecting axons. Axons in these regions also expressed phosphorylated NFs. Subsequently, on E5 and E8, the expression of both p-JNK and phosphorylated NFs increased concomitantly in the axonal tracts in the spinal white matter. Thus, white matter expressed both p-JNK and phosphorylated NFs, whereas there was only weak expression of Cdk5. By E13, the spinal cord expression pattern of p-JNK and phosphorylated NFs had changed compared to earlier ages. Although phosphorylated NFs were still expressed in the white matter, the expression of p-JNK was decreased in axons in the white matter, whereas strong p-JNK expression appeared in cell nuclei in the gray matter. In summary, the present study revealed that the localization of p-JNK in the spinal cord changes dramatically from axons to cell nuclei during development, suggesting multiple roles of p-JNK, depending on the developmental age.
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PMID:Developmental changes in the localization of activated C-JUN N-terminal kinase (JNK/SAPK) in the chick spinal cord. 1102 3

To test the hypothesis that a complex of cyclin-dependent kinase 5 (Cdk5) and p35(nck5a) plays an important role in sprouting in the kindling rat hippocampus, we studied the changes in kinase activity, expression level and subcellular localization during kindling progression. The kinase activity in kindling rats was significantly higher than that in normal rats. The changes in kinase activity coincided with those of the p35(nck5a) expression in kindling rats. In contrast, the expression of Cdk5 was constant at all stages of kindling. Subcellular localization of Cdk5, however, changed markedly in the hippocampal neurons during kindling progression. Cdk5 translocated from axon to soma when the kinase activity was high. The phosphorylation level of tau protein was in good agreement with the Cdk5 kinase activity. In contrast, MAP kinase activity was not correlated with tau phosphorylation during kindling progression. These findings suggest that Cdk5/p35(nck5a) plays an important role in synaptic reorganization, and the translocation of Cdk5 to soma from axons is a crucial regulatory mechanism of kinase activity.
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PMID:Involvement of cyclin-dependent kinase 5/p35(nck5a) in the synaptic reorganization of rat hippocampus during kindling progression. 1112 Sep 19

We have previously shown, by using the phosphate-dependent anti-tau antibodies Tau-1 and PHF-1, that heat shock induces rapid dephosphorylation of tau followed by hyperphosphorylation in female rats. In this study, we analyzed in forebrain homogenates from female Sprague-Dawley rats the activities of extracellular signal regulated kinase 1/2 (ERK1/2), c-Jun NH(2)-terminal kinase (JNK), glycogen synthase kinase-3beta (GSK-3beta), cyclin-dependent kinase 5 (Cdk5), cAMP-dependent protein kinase A (PKA), and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) at 0 (n = 5), 3 (n = 4), 6 (n = 5), and 12 (n = 5) h after heat shock and in non-heat-shocked controls (n = 5). Immunoprecipitation kinase assays at 0 h showed suppression of the activities of all kinases except of GSK-3beta, which showed increased activity. At 3-6 h, the activities of ERK1/2, JNK, Cdk5, and GSK-3beta toward selective substrates were increased; however, only JNK, Cdk5, and GSK-3beta but not ERK1/2 were overactivated toward purified bovine tau. At 3-6 h, kinase assays specific for PKA and CaMKII showed no increased activity toward either tau or selective substrates. All of eight anti-tau antibodies tested showed dephosphorylation at 0 h and hyperphosphorylation at 3-6 h, except for 12E8, which showed hyperphosphorylation also at 0 h. Immunoblot analysis using activity-dependent antibodies against ERK1/2, JNK, and GSK-3beta confirmed the above data. Increased activation and inhibition of kinases after heat shock were statistically significant in comparison with controls. Because tau is hyperphosphorylated in Alzheimer disease these findings suggest that JNK, GSK-3beta, and Cdk5 may play a role in its pathogenesis.
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PMID:tau kinases in the rat heat shock model: possible implications for Alzheimer disease. 1112 Oct 21

Niemann-Pick type C (NPC) disease is characterized by an accumulation of cholesterol in most tissues and progressive neurodegeneration with the formation of neurofibrillary tangles. Neurofibrillary tangles are composed of paired helical filaments (PHF), a major component of which is the hyperphosphorylated tau. In this study we used NPC heterozygous and NPC homozygous mouse brains to investigate the molecular mechanism responsible for tauopathy in NPC. Immunoblot analysis using anti-tau antibodies (Tau-1, PHF-1, AT-180, and AT-100) revealed site-specific phosphorylation of tau at Ser-396 and Ser-404 in the brains of NPC homozygous mice. Mitogen-activated protein kinase, a potential serine kinase known to phosphorylate tau, was activated, whereas other serine kinases such as glycogen synthase kinase-3beta and cyclin-dependent kinase 5 were inactive. Morphological examination demonstrated that a number of neurons, the perikarya of which strongly immunostained with PHF-1, exhibited polymorphorous cytoplasmic inclusion bodies and multi-concentric lamellar-like bodies. Importantly, the accumulation of intracellular cholesterol in NPC mouse brains was determined to be a function of age. From these results we conclude that abnormal cholesterol metabolism due to the genetic mutation in NPC1 may be responsible for activation of the mitogen-activated protein kinase-signaling pathway and site-specific phosphorylation of tau in vivo, leading to tauopathy in NPC.
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PMID:Site-specific phosphorylation of tau accompanied by activation of mitogen-activated protein kinase (MAPK) in brains of Niemann-Pick type C mice. 1115 66


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