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)

Mutations in the parkin gene cause autosomal-recessive, juvenile-onset parkinsonism, and parkin dysfunction may also play a role in the pathogenesis of sporadic Parkinson disease (PD). Although its precise function remains largely unknown, parkin seems to play a neuroprotective role. Several studies indicate that changes in parkin solubility induced by post-translational modifications, such as S-nitrosylation or dopamine modification, comprise one mechanism of parkin inactivation associated with disease. Protein phosphorylation events have recently been linked to the molecular mechanism(s) underlying PD, but the role of this post-translational modification for parkin function has remained unclear. Here we report that compound phosphorylation of parkin by both casein kinase I and cyclin-dependent kinase 5 (cdk5) decreases parkin solubility, leading to its aggregation and inactivation. Combined kinase inhibition partially reverses the aggregative properties of several pathogenic point mutants in cultured cells. Enhanced parkin phosphorylation is detected in distinct brain areas of individuals with sporadic PD and correlates with increases in the levels of p25, the activator of cdk5. These findings indicate that casein kinase I and cdk5 may represent novel combinatorial therapeutic targets for treating PD.
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PMID:Combined kinase inhibition modulates parkin inactivation. 1905 41

Recent studies demonstrate that activation of Ca(2+)-permeable N-methyl-D-aspartate (NMDA) receptors upregulates phosphorylation of mitogen-activated protein kinases (MAPKs) in heterologous cells and neurons. In cultured rat striatal neurons, the present work systematically evaluated the role of a number of protein kinases in forming a signaling cascade transducing NMDA receptor signals to MAPKs. It was found that a brief NMDA application consistently induced rapid and transient phosphorylation of the extracellular signal-regulated kinase 1/2 (ERK1/2), a best characterized subclass of MAPKs. This ERK1/2 phosphorylation was resistant to the inhibition of protein kinase C, p38 MAPK, cyclin-dependent kinase 5, receptor tyrosine kinase (epidermal growth factor receptors), or non-receptor tyrosine kinases (including Src) by their selective inhibitors. However, the increase in ERK1/2 phosphorylation was partially blocked by a protein kinase A (PKA) inhibitor. The inhibitors for Ca(2+)/calmodulin-dependent protein kinase (CaMK) or phosphatidylinositol 3-kinase (PI3-kinase) completely blocked the NMDA-stimulated ERK1/2 phosphorylation. In an attempt to characterize the sequential role of CaMK and PI3-kinase, we found that NMDA increased PI3-kinase phosphorylation on Tyr(508), which kinetically corresponded to the ERK1/2 phosphorylation and was blocked by the CaMK inhibitor. These results indicate that the protein kinases are differentially involved in linking NMDA receptors to ERK1/2 in striatal neurons.
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PMID:Regulation of extracellular signal-regulated kinase phosphorylation in cultured rat striatal neurons. 1905 70

H1 histones are progressively phosphorylated during the cell cycle. The number of phosphorylated sites is zero to three in late S phase and increases to five or six in late G2 phase and M phase. It is assumed that this phosphorylation modulates chromatin condensation and decondensation, but its specific role remains unclear. Recently, it was shown that the somatic H1 histone subtype H1.5 becomes pentaphosphorylated during mitosis, with phosphorylated threonine 10 being the last site to be phosphorylated. We have generated an antiserum specific for human H1.5 phosphorylated at threonine 10. Immunofluorescence labeling of HeLa cells with this antiserum revealed that the phosphorylation at this site appears in prometaphase and disappears in telophase, and that this hyperphosphorylated form of H1.5 is mainly chromatin-bound in metaphase when chromatin condensation is maximal. In search of the kinase responsible for the phosphorylation at this site, we found that threonine 10 of H1.5 can be phosphorylated by glycogen synthase kinase-3 in vitro, but not by cyclin-dependent kinase 1/cyclin B and cyclin-dependent kinase 5/p35, respectively. Furthermore, addition of specific glycogen synthase kinase-3 inhibitors led to a reduction in phosphorylation at this site both in vivo and in vitro.
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PMID:M phase-specific phosphorylation of histone H1.5 at threonine 10 by GSK-3. 1913 8

Alzheimer disease (AD) is a neurodegenerative disorder characterized by neuronal loss, dementia and pain. Two main protein aggregates, extracellular (senile plaques, SP) and intracellular (neurofibrillary tangles, NFT), are associated with AD. NFT are mainly composed of hyperphosphorylated microtubule-associated protein tau. Nowadays several protein kinases have been implicated in the phosphorylation of tau, including glycogen synthase kinase 3 beta (GSK3beta), MAP kinase, protein kinase A and cyclin-dependent kinase 5 (Cdk5). A deregulation in the activity of Cdk5 has been postulated to participate in the abnormal tau hyperphosphorylation in AD. Activation of Cdk5 occurs after its association with p35, a neuron-specific activator, predominantly in the nervous system. Therefore, in this study we used the tetracycline transactivator system to increase p35/GFP in neuronal cells, treated with amyloid beta 1-42 (Abeta(1-42)) peptide. These cells showed an increase of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and cleaved caspase-3 staining, indicating increased apoptosis of neuronal cells. This effect could be reversed by the addition of tetracycline in the culture medium, suggesting synergistic effects of p35 over-expression and Abeta treatment in the apoptosis of neuronal cells. These results represent a linkage between amyloidogenic and cdk5 pathways leading to apoptosis of neuronal cells.
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PMID:Cyclin-dependent kinase 5 activator p35 over-expression and amyloid beta synergism increase apoptosis in cultured neuronal cells. 1936 24

Abnormalities in molecular signalling have been implicated in neurodegeneration. It is emerging that glycogen synthase kinase-3 (GSK-3) is a key signalling molecule that induces neurodegeneration and deficits in memory formation related to Alzheimer's disease (AD). Early stages of AD are associated with deficits in memory formation before neuronal cell death is detectable. Recent studies in rodents have suggested that these impairments in memory formation might result from increased GSK-3 signalling, because enhanced GSK-3 activity impairs hippocampal memory formation. GSK-3 activity blocks synaptic long-term potentiation and induces long-term depression. Furthermore, increased GSK-3 signalling is likely to be a key contributor to the formation of the pathological hallmarks in AD, neurofibrillary tangles (NFTs) and amyloid plaques. Recent studies with mouse models have indicated that GSK-3, but not cyclin-dependent kinase 5, is critical for hyperphosphorylation of the cytoskeletal protein tau, which is the prerequisite for NFT formation in AD. Furthermore, increased GSK-3 signalling in AD mice causes abnormal processing of the amyloid precursor protein so that amyloid peptide production augments and neurotoxicity is induced. Taken together, the current evidences suggest that increased GSK-3 signalling may be responsible for the deficits in memory formation in early stages of AD and neurodegeneration in later stages of the disease.
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PMID:GSK-3: a key player in neurodegeneration and memory. 1939 Nov 64

Inhibitors of HMG-CoA reductase (statins) are widely used medications for reduction of cholesterol levels. Statin use significantly reduces risk of cardiovascular disease but has also been associated with lower risk of other diseases and conditions, including dementia. However, some reports suggest that statins also have detrimental effects on the brain. We provide evidence that simvastatin and pravastatin have significantly different effects on expression of genes related to neurodegeneration in astrocytes and neuroblastoma (SK-N-SH) cells in culture. Simvastatin significantly reduced expression of ABCA1 in astrocytes and neuroblastoma cells (by 79% and 97%, respectively; both P < 0.001). Pravastatin had a similar but attenuated effect on ABCA1 in astrocytes (-54%, P < 0.001) and neuroblastoma cells (-70%, P < 0.001). Simvastatin reduced expression of apolipoprotein E in astrocytes (P < 0.01). Furthermore, both statins reduced expression of microtubule-associated protein tau in astrocytes (P < 0.01), while both statins increased its expression in neuroblastoma cells (P < 0.01). In SK-N-SH cells, simvastatin significantly increased cyclin-dependent kinase 5 and glycogen synthase kinase 3beta expression, while pravastatin increased amyloid precursor protein expression. Our data suggest that simvastatin and pravastatin differentially affect expression of genes involved in neurodegeneration and that statin-dependent gene expression regulation is cell type specific.
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PMID:Differential effects of simvastatin and pravastatin on expression of Alzheimer's disease-related genes in human astrocytes and neuronal cells. 1946 Nov 18

The function of the D(3) dopamine (DA) receptor remains ambiguous largely because of the lack of selective D(3) receptor ligands. To investigate the function and intracellular signaling of D(3) receptors, we established a PC-12/hD3 clone, which expresses the human D(3) DA receptor in a DA producing cell line. In this model, we find that the D(3) receptor functions as an autoreceptor controlling neurotransmitter secretion. Pre-treatment with 3,6a,11, 14-tetrahydro-9-methoxy-2 methyl-(12H)-isoquino[1,2-b] pyrrolo[3,2-f][1,3] benzoxanzine-1-carboxylic acid, a D(3) receptor preferring agonist, dose-dependently suppressed K+-evoked [3H]DA release in PC-12/hD3 cells but not in the control cell line. This effect was prevented by D(3) receptor preferring antagonists GR103691 and SB277011-A. Furthermore, activation of D(3) receptors significantly inhibits forskolin-induced cAMP accumulation and leads to transient increases in phosphorylation of cyclin-dependent kinase 5 (Cdk5), dopamine and cAMP-regulated phosphoprotein of M(r) 32 000 and Akt. Because we observed differences in Cdk5 phosphorylation as well as Akt phosphorylation after DA stimulation, we probed the ability of Cdk5 and phosphatidylinositol-3 kinase (PI3K) to influence DA release. Cdk5 inhibitors, roscovitine, or olomoucine, but not the PI3K inhibitor wortmannin, blocked the D(3) receptor inhibition of DA release. In a complimentary experiment, over-expression of Cdk5 potentiated D(3) receptor suppression of DA release. Pertussis toxin, 3-[(2,4,6-trimethoxyphenyl)methylidenyl]-indolin-2-one and cyclosporine A also attenuated D(3) receptor-mediated inhibition of DA release indicating that this phenomenon acts through Gi/oalpha and casein kinase 1, and phosphatase protein phosphatase 2B (calcineurin), respectively. In support of previous data that D(3) DA receptors reduce transmitter release from nerve terminals, the current results demonstrate that D(3) DA receptors function as autoreceptors to inhibit DA release and that a signaling pathway involving Cdk5 is essential to this regulation.
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PMID:The D(3) dopamine receptor inhibits dopamine release in PC-12/hD3 cells by autoreceptor signaling via PP-2B, CK1, and Cdk-5. 1952 35

Increasing evidence is demonstrating that drugs affecting dopamine levels in the brain induce cytoskeletal modifications. These evolving changes may impact neuronal synaptic plasticity as cytoskeletal constituents are involved in the maintenance of dendritic processes, and any alterations in their stability could influence major cellular compartments of neurons, such as dendrites, spines and synapses. Here, we describe a molecular chain of events that links dopamine D1 receptor activation to hyperphosphorylation of the microtubule-associated protein tau, which is normally involved in microtubules stabilization. We show, in SK-N-MC cells and rat striatal sections, that phosphorylation of tau at serines 199-202 and 214 appears to be mediated through activation of calcium-dependent intracellular mechanism, subsequent to D1 receptor-induced cAMP-dependent protein kinase A (PKA). We demonstrate, using pharmacological tools, that PKA activation causes increase of calcium levels, leading to cyclin-dependent kinase 5 activation by calpain proteolysis of p35 to p25 and glycogen synthase kinase 3beta activation by its phosphorylation at tyrosine 216. The D2 receptor agonism or lowering cAMP levels has no effect in our experimental settings. Moreover, we do not observe any association between phosphorylated tau and cellular damage. These data unravel novel mechanisms of tau hyperphosphorylation during G-protein-coupled receptor activation and are the first to show that stimulation of D1 receptors could have a profound influence on the neuronal cytoskeletal constituent tau.
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PMID:Dopamine D1 receptor activation induces tau phosphorylation via cdk5 and GSK3 signaling pathways. 1959 49

Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD), the combination with dopamine switches LTD to long-term potentiation (LTP), which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32), as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA), protein phosphatase 2A (PP2A), and the phosphorylation site at threonine 75 of DARPP-32 (Thr75) served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B)-CK1 (casein kinase 1)-Cdk5 (cyclin-dependent kinase 5)-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP). The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The present model elucidated the mechanisms involved in bidirectional regulation of corticostriatal synapses and will allow for further exploration into causes and therapies for dysfunctions such as drug addiction.
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PMID:A kinetic model of dopamine- and calcium-dependent striatal synaptic plasticity. 2016 76

The signaling mechanisms underlying cell differentiation have been extensively studied with the use of rat PC12 cells as a model system. Nerve growth factor (NGF) is a trophic factor inducing PC12 cell differentiation through the activation of the p35/cyclin-dependent kinase 5 (Cdk5) complex. It has been reported that adenylyl cyclase activation and cAMP production may be involved in NGF-dependent actions. Our previous results indicate that cAMP activates the p35/Cdk5 complex in reproductive cells. Therefore, the role of cAMP in NGF-triggered p35/Cdk5 activation and PC12 differentiation was interesting to explore. Our results indicate that roscovitine, a molecular inhibitor of Cdk5, blocks cAMP-triggered PC12 differentiation, which was evaluated by neurite initiation, a decrease in proliferation, and cell cycle G(1) arrest. The following data show that cAMP treatment increased Cdk5 activity through p35 upregulation. cAMP downstream components, protein kinase A (PKA) and phosphorylated cAMP response element binding protein (CREB), are involved in this regulation. The immunocytochemical results indicate that PKA inhibition disrupted cAMP-triggered p35/Cdk5 localization in PC12 cells. In addition, adenylyl cyclase inhibition was found to diminish NGF-induced intracellular cAMP production, CREB phosphorylation, and p35 expression. The cAMP antagonist and the PKA inhibitors reduced NGF-induced p35 expression. Finally, NGF-triggered PC12 differentiation was partially decreased by adenylyl cyclase or PKA inhibitors. In conclusion, these results demonstrate that cAMP may play a role in NGF-p35/Cdk5-dependent PC12 differentiation.
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PMID:Involvement of cAMP in nerve growth factor-triggered p35/Cdk5 activation and differentiation in PC12 cells. 2046 73


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