Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase Cmu (PKCmu), also named protein kinase D, is an unusual member of the PKC family that has a putative transmembrane domain and pleckstrin homology domain. This enzyme has a substrate specificity distinct from other PKC isoforms (Nishikawa, K., Toker, A., Johannes, F. J., Songyang, Z., and Cantley, L. C. (1997) J. Biol. Chem. 272, 952-960), and its mechanism of regulation is not yet clear. Here we show that PKCmu forms a complex in vivo with a phosphatidylinositol 4-kinase and a phosphatidylinositol-4-phosphate 5-kinase. A region of PKCmu between the amino-terminal transmembrane domain and the pleckstrin homology domain is shown to be involved in the association with the lipid kinases. Interestingly, a kinase-dead point mutant of PKCmu failed to associate with either lipid kinase activity, indicating that autophosphorylation may be required to expose the lipid kinase interaction domain. Furthermore, the subcellular distribution of the PKCmu-associated lipid kinases to the particulate fraction depends on the presence of the amino-terminal region of PKCmu including the predicted transmembrane region. These results suggest a novel model in which the non-catalytic region of PKCmu acts as a scaffold for assembly of enzymes involved in phosphoinositide synthesis at specific membrane locations.
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PMID:Association of protein kinase Cmu with type II phosphatidylinositol 4-kinase and type I phosphatidylinositol-4-phosphate 5-kinase. 972 41

Protein kinase Cmu (PKCmu) represents a new subtype of the PKC family characterized by the presence of a pleckstrin homology (PH) domain and an amino-terminal hydrophobic region. In order to analyse the potential role of PKCmu in signal-transduction pathways, stable PKCmu transfectants were established with human and murine cell lines. All transfectants showed a reduced sensitivity to tumor-necrosis-factor (TNF)-induced apoptosis, which correlated with the amount of transgene expressed and with an enhanced basal transcription rate of NF-kappaB-driven genes including the inhibitor of apoptosis protein 2 (cIAP2) and TNF-receptor-associated protein 1 (TRAF1). Sensitivity to apoptosis induced by the lipid mediator ceramide was unchanged in PKCmu transfectants. In support of a PKCmu action on NF-kappaB, we show enhancement and downregulation of TNF-induced expression of a NF-kappaB-dependent reporter gene by transient overexpression of wild-type and kinase-negative mutants of PKCmu, respectively. Interestingly, no significant changes were found in an electrophoretic mobility shift assay, indicative of PKCmu action downstream of IkappaB degradation, probably by modulation of the transactivation capacity of NF-kappaB. The dominant negative action of the kinase-negative mutant further suggest a regulatory role of PKCmu for NF-kappaB-dependent gene expression.
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PMID:Protein kinase Cmu downregulation of tumor-necrosis-factor-induced apoptosis correlates with enhanced expression of nuclear-factor-kappaB-dependent protective genes. 979 1

The program of biochemical and molecular events necessary for commitment to erythroid cell differentiation is particularly well characterized in murine Friend erythroleukemia cell lines. Commitment to hemoglobin synthesis in response to a variety of chemical inducers, including hexamethylene bisacetamide and dimethyl sulfoxide is completed by 24 h and proceeds to terminal differentiation by 96 h. Phorbol 12-myristate 13-acetate, a classical tumor promoter phorbol ester that binds to protein kinase C, blocks differentiation in a reversible manner, suggesting an important role for protein kinase C signaling pathways. The classical protein kinase C isoforms alpha, betaI, and betaII, play distinct roles in the transduction of proliferative and differentiative signals in human, as well as in murine, erythroleukemia cells. Protein kinase Calpha has been implicated in differentiation of human erythroleukemia cells although its translocation to the nucleus has not been observed. Taking advantage of the ability of phorbol 12-myristate 13-acetate to block differentiation in Friend erythroleukemia cells, we determined the localization of the predominant protein kinase C isoforms alpha and betaI during differentiation and in response to their blockade. The ability of phorbol myristate acetate to preferentially diminish protein kinase Calpha-protein localization to the nucleus by 24 h and thereby block differentiation induced by hexamethylene bisacetamide was paralleled by the ability of protein kinase Calpha antisense transfection to block differentiation. In addition, beta-globin transcription, assessed by polymerase chain reaction, was significantly decreased in protein kinase Calpha antisense-transfected cells compared to that seen in vector transfected ones. Taken together, these data suggest an important temporal role for nuclear protein kinase Calpha localization in Friend erythroleukemia cell differentiation.
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PMID:Protein kinase calpha is an effector of hexamethylene bisacetamide-induced differentiation of Friend erythroleukemia cells. 992 50

Recombinant protein segments from a metabotropic glutamate receptor and from an odorant receptor were used as substrates in protein kinase C phosphorylation assays. Protein kinase Cbeta and delta phosphorylated an intracellular consensus phosphorylation site in the metabotropic glutamate receptor. Only protein kinase Cdelta phosphorylated a novel extracellular consensus phosphorylation site in the odorant receptor. These results suggest differential regulation of these receptors by protein kinase C isotypes.
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PMID:Protein kinase Cbeta and delta selectively phosphorylate odorant and metabotropic glutamate receptors. 1040 Apr 48

Previously we reported that a phorbol ester, phorbol 12, 13-dibutyrate (PDBu), increased the release of human growth hormone-binding protein (hGH-BP) in IM-9 cells, and that this phorbol ester-enhanced release was mediated by protein kinase Ca (PKCalpha). In the present study, the mechanisms of the phorbol ester-enhanced hGH-BP release were further investigated. Treatment of IM-9 cells with PDBu did not increase hGH-BPs (55-60 kDa) in the intracellular soluble fraction. When the cells were treated with trypsin to remove human growth hormone receptors (hGHRs) on the cell surface after stimulation, no hGH-BPs were detected in the culture supernatants, nor did treatment with bafilomycin A1 or chloroquine affect the PDBu-enhanced hGH-BP release. These results suggest that hGH-BPs released by PDBu stimulation are derived from cell surface hGHRs and not generated within the cells. Protein kinase inhibitors with broad specificities, K-252a and K-252b, inhibited the PDBu-enhanced release with almost the same dose-dependency, although only a trace amount of K-252b was incorporated into IM-9 cells than K-252a, suggesting that K-252b probably inhibits an ecto-kinase extracellularly. PDBu actually enhanced the phosphorylation of several extracellular proteins, and this enhanced phosphorylation was completely inhibited by K-252b treatment. Moreover, the PKCalpha-specific inhibitor bisindolylmaleimide III which inhibits PDBu enhanced hGH-BP release inhibited the PDBu-enhanced phosphorylation of extracellular proteins. On the other hand, the impermeable PKC inhibitor PKC inhibitor peptide 19-31 did not inhibit PDBu-enhanced release, suggesting that the target PKCalpha for PDBu is not present on the extracellular surface. Taken together, these results suggest that, in addition to intracellular PKCalpha, activation of an undefined ecto-kinase may also be involved in the PDBu-enhanced hGH-BP release.
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PMID:Role of ecto-kinase in phorbol ester-enhanced growth hormone-binding protein release from human IM-9 cells. 1043 24

Protein kinase (PK) C is an increasingly diverse family of enzymes that has been implicated in a range of cellular functions within the eosinophil. Using isoform-specific polyclonal antibodies, we have explored the expression of PKC isoforms in circulating eosinophils. Initial studies demonstrated the presence of the alpha, betaI, betaII, and zeta and the low-level expression of the delta, epsilon, iota, and micro isoforms but no detectable expression of the gamma, eta, and theta isoforms in both normal and asthmatic subjects. There was no difference in the total protein expression between these two groups. Subsequent studies examined the expression and activation of PKC isoforms in circulating eosinophils from asthmatic patients before and 24 h after a late asthmatic response to an inhaled allergen. Cellular fractionation showed PKC-alpha and PKC-betaII to be mainly located in the cytosol, whereas PKC-betaI was constitutively more expressed in the membrane. No changes in expression or subcellular localization of these isoforms were seen after allergen challenge. In contrast, PKC-zeta expression was increased after allergen challenge, and we demonstrated a significant PKC-zeta translocation to the membrane, in keeping with activation of the enzyme. Our results suggest that 24 h after allergen exposure of asthmatic patients, there is increased expression and activation of eosinophil PKC-zeta that correlates with late asthmatic responses recorded between 4 and 10 h postallergen challenge.
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PMID:Expression and activation of protein kinase C-zeta in eosinophils after allergen challenge. 1044 16

Spreading depression is a wave of sustained depolarization challenging the energy metabolism of the cells without causing irreversible damage. In the ischaemic brain, sreading depression-like depolarization contributes to the evolution of ischaemia to infarction. The depolarization is propagated by activation of N-methyl-D-aspartate receptors, but changes in signal transduction downstream of the receptors are not known. Because protein phosphorylation is a general mechanism whereby most cellular processes are regulated, and inhibition of N-methyl-D-aspartate receptors or protein kinase C is neuroprotective, the expression of protein kinase C subspecies in spreading depression was examined. Cortical treatment with KCl induced an upregulation of protein kinase Cdelta and zeta messenger RNA at 4 and 8 h, whereas protein kinase Calpha, beta, gamma and epsilon did not show significant changes. The gene induction was the strongest in layers 2 and 3, and was followed by an increased number of protein kinase Cdelta-immunoreactive neurons. Protein kinase Cdelta and zeta inductions were inhibited by pretreatment with an N-methyl-D-aspartate receptor antagonist, dizocilpine maleate, which also blocked spreading depression propagation, and with dexamethasone, which acted without blocking the propagation. Quinacrine, a phospholipase A2 inhibitor, reduced only protein kinase C5 induction. In addition, N(G)(-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, did not influence protein kinase Cdelta or zeta induction, whereas 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate receptor antagonist, and the cyclo-oxygenase inhibitors indomethacin and diclophenac tended to increase gene expression. The data show that cortical spreading depression induces Ca2(+)-independent protein kinase C subspecies delta and zeta, but not Ca(2+)-dependent subspecies, through activation of N-methyl-D-aspartate receptors and phospholipase A2. Even though the signal pathway is similar to the induction described previously in ischaemia for genes implicated in delayed neuronal death, the gene inductions observed here are not necessarily pathogenetic, but may represent a general reaction to metabolic stress.
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PMID:Spreading depression induces expression of calcium-independent protein kinase C subspecies in ischaemia-sensitive cortical layers: regulation by N-methyl-D-aspartate receptors and glucocorticoids. 1047 63

Application of brain-derived neurotrophic factor (BDNF) to hippocampal neurons has profound effects on glutamatergic synaptic transmission. Both pre- and postsynaptic actions have been identified that depend on the age and type of preparation. To understand the nature of this diversity, we have begun to examine the mechanisms of BDNF action in cultured dissociated embryonic hippocampal neurons. Whole-cell patch-clamp recording during iontophoretic application of glutamate revealed that BDNF doubled the amplitude of induced inward current. Coexposure to BDNF and the NMDA receptor antagonist AP-5 markedly reduced, but did not entirely prevent, the increase in current. Coexposure to BDNF and ifenprodil, an NR2B subunit antagonist, reproduced the response observed with AP-5, suggesting BDNF primarily enhanced activity of NR2B-containing NMDA receptors with a lesser effect on non-NMDA receptors. Protein kinase involvement was confirmed with the broad spectrum inhibitor staurosporine, which prevented the response to BDNF. PKCI19-31 and H-89, selective antagonists of PKC and PKA, had no effect on the response to BDNF, whereas autocamtide-2-related inhibitory peptide, an antagonist of CaM kinase II, reduced response magnitude by 60%. These results demonstrate the predominant role of a specific NMDA receptor subtype in BDNF modulation of hippocampal synaptic transmission.
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PMID:Blockade of NR2B-containing NMDA receptors prevents BDNF enhancement of glutamatergic transmission in hippocampal neurons. 1049 7

Protein kinase Calpha (PKCalpha) is one of six PKC isoforms expressed in keratinocytes of mouse epidermis. To gain an understanding of the role of epidermal PKCalpha, we have localized its expression to specific cells of normal mouse skin and examined the effect of keratin 5 (K5) promoter directed expression of PKCalpha in transgenic mice. In normal mouse skin, PKCalpha was extensively expressed in the outer root sheath (ORS) keratinocytes of the anagen hair follicle and weakly expressed in keratinocytes of interfollicular epidermis. K5-targeted expression of PKCalpha to epidermal basal keratinocytes and follicular ORS keratinocytes resulted in a tenfold increase in epidermal PKCalpha. K5-PKCalpha mice exhibited no abnormalities in keratinocyte growth and differentiation in the epidermis. However, a single topical treatment with the PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in a striking inflammatory response characterized by edema and extensive epidermal infiltration of neutrophils that formed intraepidermal microabscesses in the epidermis. Compared to TPA-treated wild-type mice, the epidermis of TPA-treated K5-PKCalpha mice displayed increased expression of cyclooxygenase-2 (COX-2), the neutrophil chemotactic factor macrophage inflammatory protein-2 (MIP-2) mRNA and the proinflammatory cytokine TNFalpha mRNA but not IL-6 or IL-1alpha mRNA. To determine if K5-PKCalpha mice display an altered response to TPA-promotion, 7, 12-dimethylbenz[a]anthracene-initiated K5-PKCalpha mice and wild-type mice were promoted with TPA. No differences in papilloma incidence or multiplicity were observed between K5-PKCalpha mice and wild-type littermates. These results demonstrate that the overexpression of PKCalpha in epidermis increases the expression of specific proinflammatory mediators and induces cutaneous inflammation but has little to no effect on epidermal differentiation, proliferation or TPA tumor promotion.
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PMID:Overexpression of protein kinase C-alpha in the epidermis of transgenic mice results in striking alterations in phorbol ester-induced inflammation and COX-2, MIP-2 and TNF-alpha expression but not tumor promotion. 1050 98

We previously reported that the glycoprotein extracted from aloe strongly inhibited the mediator releases caused by the activation of guinea pig lung mast cells. Therefore, this study aimed to purify a single component that has an antiallergic effect from crude aloe extract and then to assess the effects of aloe single component (alprogen) on the mechanism of mediator releases caused by the mast cell activation. We purified aloe extracts by using various columns. We also purified mast cells from guinea pig lung tissues by using enzyme digestion, rough and discontinuous density Percoll gradient. Mast cells were sensitized with IgG(1) (anti-ovalbumin) and challenged with ovalbumin. Histamine was assayed by using a fluorometric analyzer and leukotrienes by radioimmunoassay. [Ca(2+)](i) level was analyzed by using a confocal laser scanning microscope. Protein kinase activity was determined by the protein phosphorylated with [gamma-(32)P]ATP. The phospholipase D activity was assessed by the labeled phosphatidylalcohol. The amount of mass 1,2-diacylglycerol (DAG) was measured by the [(3)H]DAG produced when prelabeled with [(3)H]myristic acid. Phospholipase A(2) activity was determined by measuring the lyso-phosphatidylcholine released from the labeled phospholipids. Alprogen significantly decreased histamine and leukotriene releases and blocked completely Ca(2+) influx during mast cell activation. The protein kinase C and phospholipase D activities were decreased by alprogen in dose-dependent manner. Alprogen inhibited mass DAG formation and the phospholipase A(2) activity during mast cell activation. The data suggest that alprogen purified from aloe inhibits multiple signals as well as blocking Ca(2+) influx caused by mast cells activated with specific antigen-antibody reactions and that then the inhibition of histamine and leukotriene release follows.
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PMID:Inhibitory mechanism of aloe single component (alprogen) on mediator release in guinea pig lung mast cells activated with specific antigen-antibody reactions. 1060 37


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