Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An initial event in T cell activation is the specific adherence of T cells via their T cell receptor to the MHC peptide complex. We have studied this adherence by incubating T cells with preformed HLA DR4Dw4 peptide complexes attached to a solid support. Adherence of sodium 51Cr-labeled T cell clones specific for the influenza hemagglutinin peptide, HA 307-319, was maximal after 15 min and was specific for the HLA DR4Dw4-HA 307-319 complex. The binding was temperature dependent and could be blocked with azide or protein kinase C inhibitors, indicating that for adherence the T cells need to be metabolically active and have a functioning protein kinase C pathway. The adherence could be blocked with CD4- or CD3-reactive murine mAb, suggesting that the TCR and CD4 molecules work in concert to induce strong adherence to the HLA DR4Dw4-HA 307-319 complex. A subsequent event in T cell activation is proliferation, which is thought to need additional proteins such as IL-1 or other adhesion molecules. MHC peptide complexes coated on microtiter plates also induced proliferation in the human T cell clones. Removal of any monocytes by treatment of human T cell clones with anti-CD14 in conjunction with C, followed by purification over a nylon wool column, did not abrogate proliferation. After prolonged culture of the T cell clones in plates coated with peptide-pulsed HLA DR4Dw4 in the presence of IL-2, the T cell clones continued to proliferate in response to peptide. These results suggest that human T cell clones do not require a second signal from a monocyte or other APC to proliferate.
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PMID:Purified HLA class II peptide complexes can induce adherence and activation of peptide-specific human T cell clones. 153 49

The growth of influenza virus A/PR/8/34 in MDCK cells was inhibited by 1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride (H7) which is a potent inhibitor of protein kinase C, but not by an effective inhibitor of cyclic nucleotide-dependent protein kinases. Analysing the inhibitory effect of H7 during the replication cycle of influenza virus, we found that the primary transcripts were sufficiently synthesized in infected cells exposed to H7. The primary transcripts synthesized in the presence and absence of H7 were active in directing the synthesis of viral polypeptides both in a cell-free system and in the system containing H7. In the system where infected cells were exposed to H7, the viral positive-sense RNAs were also significantly amplified 6 h after infection. However, the synthesis of viral proteins other than nucleoprotein from viral primary or amplified (secondary) mRNAs was extremely restricted. The synthesis of host cellular proteins in mock-infected cells was significantly retained in the presence of H7. These results suggest that the selective inhibition of influenza virus translation following the transcription of viral mRNA was induced by H7 in infected cells.
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PMID:Inhibitory effect of protein kinase C inhibitor on the replication of influenza type A virus. 169 25

This paper investigates the effects of tumor vaccines on T cell proliferation induced by 12-0 tetradecanoylphorbol-13-acetate (TPA). Viral oncolysate (VO) tumor vaccines containing inactivated influenza virus A significantly inhibited TPA-induced T cell proliferation. In contrast, a control tumor vaccine (CO) that contained the same cellular components as VO but lacked influenza virus did not affect the TPA-induced proliferation. These effects were also observed with peripheral blood mononuclear cells (PBMC) from ovarian cancer patients, although VO and CO each induced significant and similar levels of proliferation in these cells in the absence of TPA. Protein kinase C (PKC) is a pivotal enzyme in signal transduction pathways that control cell proliferation, and TPA is a specific activator of PKC. VO and CO showed differential effects on the inhibition of purified protein kinase C (PKC). These studies demonstrate the antagonistic effects of different tumor vaccines on T lymphocyte proliferation and suggest that influenza virus A or virus-modified cellular components may interfere with signal transduction in the immune cells of the recipient of the tumor vaccine.
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PMID:Immunological effects of tumor vaccines: III. Influenza virus oncolysates inhibit the TPA induced activation of peripheral blood mononuclear cells. 193 17

We have previously demonstrated that influenza A virus (IAV) stimulates the human neutrophil through phospholipase C activation. With the use of the fluorescent indicator 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF), cytoplasmic acidification and subsequent alkalinization are shown to accompany this activation. These responses are not inhibited by pertussis toxin (PT). The alkalinization is mediated largely *but not entirely) by the Na(+)-H+ antiporter and is not initiated, or modulated, by the IAV-induced cytosolic Ca2+ (Cai2+) rise. Rather, protein kinase C (PKC) is likely the mediator of cell alkalinization, based on studies using the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7). The acidification can be dissociated from the alkalinization response, which is also independent of Cai2+ fluxes and of PKC. Both pHi responses can be dissociated from the respiratory burst. Cytosolic alkalinization and acidification seem to reflect two independently mediated responses of the activated neutrophil, the former resulting ultimately from phospholipase activation and the latter from other activities that are not yet fully characterized.
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PMID:Human neutrophil stimulation by influenza virus: relationship of cytoplasmic pH changes to cell activation. 211 68

Neutrophil dysfunction consequent to influenza A virus infection has been described in vivo and in vitro and may contribute to the serious bacterial sequelae which occur in influenza-infected hosts. On the premise that such dysfunction may represent a form of "deactivation," we sought to characterize neutrophil activation by the virus in comparison with other agonists. The virus induces a respiratory burst in which H2O2 (but not O2-) are formed. Preceding the respiratory burst, a rise in intracellular calcium (Ca2+i) is noted, but both responses are nearly independent of extracellular Ca2+, unlike those elicited by the other well-characterized Ca2+-dependent agonists, formyl-methyl-leucyl-phenylalanine (FMLP), or Concanavalin-A (Con-A). The Ca2+ increase is paralleled by IP3 generation, implying that it is the result of phospholipase C (PLC) activation. The virus also elicits neutrophil membrane depolarization, which is independently mediated from the Ca2+ increase and respiratory burst and may reflect protein kinase C (PK-C) activation. Virus-induced responses are insensitive to pertussis toxin (PT); cholera toxin does inhibit these responses but in a nonspecific manner. Thus, although influenza virus activates PLC in neutrophils, it does so in a PT-insensitive manner and does not elicit or require a discernible Ca2+ influx to generate a respiratory burst response. In aggregate, the data indicate that influenza A virus activates neutrophils in a manner distinct from that of other well-described neutrophil agonists. These results illustrate the diversity of neutrophil activation mechanisms and support the notion that further characterization of this pathway may facilitate understanding of neutrophil dysfunction induced by the virus.
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PMID:Characterization of influenza A virus activation of the human neutrophil. 215 30

An analysis of the nucleoprotein (NP) of 29 different influenza A viruses by phosphopeptide fingerprinting revealed three prototype patterns. The first, which was a complex pattern consisting of six to seven phosphopeptides, another which was relatively simple consisted of two or three phosphopeptides, and a third one which was complex but was missing the main phosphopeptide shared by the two other patterns. Phosphoserine was the only labelled phosphamino acid detected. A tentative deduction of two of the phosphate attachment sites (serine residues at positions 3 and 473) could be made by comparison of the known amino acid sequences of the NPs of 25 strains. No correlation was found between species specificity or subtype or year of isolation of the strains. During the infectious cycle the fingerprint underwent significant changes, indicating subtle phosphorylation and dephosphorylation of the NP at various stages during viral multiplication. Most of the phosphopeptides were metabolically stable; however one major phosphopeptide, which was not found in the NP of mature virions, exhibited a high turnover (presumably serine at position 3). The phosphopeptide fingerprint could be significantly influenced in vivo by the specific stimulation of cellular protein kinase C by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate or by its inhibition with the isoquinoline sulphonamide H7.H7 specifically inhibited the replication of influenza A viruses by deregulation of viral protein synthesis without interfering with the multiplication of a parainfluenza virus (Newcastle disease virus), an alphavirus (Semliki Forest virus) or a flavivirus (West Nile). Therefore the correct phosphorylation of the NP of influenza viruses appears to be essential for influenza virus replication.
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PMID:Differential phosphorylation of the nucleoprotein of influenza A viruses. 277 38

To investigate the function of protein kinase C (PKC)-delta, we mutated its ATP binding site by converting the invariant lysine in the catalytic domain (amino acid 376) to an arginine. Expression vectors containing wild type and mutant PKC-delta cDNAs were generated either with or without an influenza virus hemagglutinin epitope tag. After expression in 32D cells by transfection, the PKC-delta ATP binding mutant (PKC-delta K376R) was not able to phosphorylate itself or the PKC-delta pseudosubstrate region-derived substrate, indicating that PKC-delta K376R was an inactive enzyme. PKC activity was inhibited by 67% in 32D cells coexpressing both PKC-delta wild type (PKC-delta WT) and PKC-delta K376R when compared to 32D cells expressing only PKC-delta WT. Mixture of PKC-delta WT and PKC-delta K376R kinase sources in vitro also reduced the enzymatic activity of PKC-delta WT. These results suggest that PKC-delta K376R competes with PKC-delta WT and inhibits PKC-delta WT phosphorylation of its in vitro substrate. While PKC-delta WT overexpressed in 32D cells demonstrated 12-O-tetradecanoylphorbol-13-acetate (TPA)-dependent translocation from the cytosolic to the membrane fraction, PKC-delta K376R was exclusively localized in the membrane fraction even prior to TPA stimulation. Unlike PKC-delta WT which was phosphorylated on tyrosine residue(s) only after TPA treatment, PKC-delta K376R was constitutively phosphorylated on tyrosine residue(s). Although exposure of PKC-delta WT transfectants to TPA induced 32D monocytic differentiation, the 32D/PKC-delta K376R transfectants were resistant to TPA-induced differentiation. Thus, expression of active PKC-delta is required to mediate 32D monocytic differentiation in response to TPA stimulation.
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PMID:Characterization of a protein kinase C-delta (PKC-delta) ATP binding mutant. An inactive enzyme that competitively inhibits wild type PKC-delta enzymatic activity. 771 39

The influenza virus hemagglutinin glycoprotein (HA) induces a vigorous B cell proliferation and Ig-synthesis by an unknown activation mechanism, which is susceptible to the inhibitory effects of anti-Ig and anti-class II mAbs. To gain further insight into the activation mode of this T cell-independent, B cell "superstimulatory" virus, we analyzed the sensitivity of H2-subtype virus-mediated B cell activation to the inhibitory effects of various signal transduction-blocking agents and compared it to the well characterized anti-mu-mediated and the LPS-employed pathway. Cyclic-AMP agonists (cAMP-analogues, pentoxifylline, cholera toxin, and forskolin) blocked HA-mediated activation of B cells only at concentrations at least 50-fold higher than required for blocking of anti-mu-induced activation. However, HA-treatment failed to induce an increase in intracellular cAMP levels in responding B cells. The B cell response to HA was highly resistant to calcineurin-inhibitory cyclosporin-A treatment and did not result in a measurable Ca2+ influx. Similarly, HA failed to induce an increase in tyrosine phosphorylations, including phosphorylation of phospholipase C gamma 2. HA-activated B cells showed an increase in membrane-associated protein kinase C activity, and depletion of protein kinase C by pretreatment of B cells with phorbol esters inhibited a subsequent activation by HA. Collectively, our results provide a new example of B cell stimulation by multivalent type-2 Ags, which seems to be mediated by a phosphatidylinositol- and Ca(2+)-independent signaling pathway.
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PMID:B cell superstimulatory influenza virus (H2-subtype) induces B cell proliferation by a PKC-activating, Ca(2+)-independent mechanism. 786 86

Bovine parainfluenza-3 (PI-3) virus inhibits oxygen-dependent bacterial killing by phagocytes, a key pulmonary defense, thus predisposing the host to intrapulmonary bacterial superinfection. PI-3 virus inhibited opsonized zymosan or PMA-activated superoxide anion (O2-) generation in bovine alveolar macrophages. The respiratory virus influenza also inhibits O2- generation by phagocytes, however, the mechanisms(s) of viral inhibition differs from PI-3. PI-3 did not trigger O2- generation before inhibition, whereas influenza triggered O2- generation before desensitization of ligand-initiated respiratory burst. PI-3 modified the twin signals of calcium and protein kinase C in alveolar macrophages. PI-3 infection increased macrophage membrane permeability to extracellular calcium, but did not inhibit calcium mobilization triggered by opsonized zymosan. These effects further distinguish bovine PI-3 from human influenza, which triggers mobilization of cell-associated calcium and inhibits calcium mobilization activated by physiologic ligands. Macrophages possessed two classes of PKC activity, a calcium/phosphatidylserine/diglyceride (Ca/PS/DG))-dependent activity and a Ca-independent, PS/DG-dependent histone IIIS phosphorylating activity. PI-3 infection selectively depleted the Ca-independent, PS/DG-dependent kinase activity but not the classical Ca/PS/DG-dependent activity. Inhibition of Ca-independent, PS/DG-dependent kinase activity and inhibition of O2- generation by PI-3 occurred at a similar viral dose and time frame, suggesting a role for this kinase in activating the respiratory burst. Inhibition of the oxygen-dependent bactericidal function of alveolar macrophages and disturbances in signal transduction may contribute to the immunosuppression and bacterial superinfection accompanying viral respiratory disease.
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PMID:Bovine parainfluenza-3 virus selectively depletes a calcium-independent, phospholipid-dependent protein kinase C and inhibits superoxide anion generation in bovine alveolar macrophages. 802 47

In polarized Madin-Darby canine kidney cells the newly synthesized plasma membrane proteins, on the exocytic pathway, are sorted in the trans-Golgi network (TGN) and delivered directly to the apical or basolateral surface. Forskolin, isobutylmethylxanthine, and dibutyryl cAMP, all known to activate protein kinase A, stimulated transport of influenza hemagglutinin (HA) from the TGN to the apical surface. The same reagents, however, did not affect the transport of HA from the endoplasmic reticulum to the Goli complex nor did they affect transport of vesicular stomatitis virus G protein from the TGN to the basolateral surface. The addition of staurosporin, a general protein kinase inhibitor, did not affect the transport of HA in nontreated cells but blocked the stimulation caused by the above reagents. Apical transport of HA was also stimulated by phorbol ester, an activator of protein kinase C. Activation of apical transport by phorbol ester as well as aluminum fluoride (Pimplikar, S. W., and Simons, K. (1993) Nature 362, 456-458) was also negated by staurosporin. These results show that in polarized Madin-Darby canine kidney cells, protein kinase A and protein kinase C selectively stimulate the apical transport.
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PMID:Activators of protein kinase A stimulate apical but not basolateral transport in epithelial Madin-Darby canine kidney cells. 803 64


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