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)

In a patient with immune thrombocytopenic purpura (ITP), we found a novel platelet-activating IgG (act-IgG) and an inhibitory IgG (inhi-IgG) that prevented activation induced by both CD9 monoclonal antibody (mAb) and the act-IgG. Purified IgG from the patient plasma caused a rise in [Ca2+]i and the aggregation of normal platelets, and bound to a 24 kD membrane protein. This aggregation was inhibited by aspirin, staurosporine, an inhibitor of protein kinase C, and F(ab')2 fragments of MALL13, a CD9 mAb. When the platelet count of this patient rose to normal range, the act-IgG disappeared. About 2 weeks later, the relapse of thrombocytopenia was observed. The purified IgG obtained in this period did not activate platelets but inhibited both the rise in [Ca2+]i and platelet aggregation stimulated by NNKY 1-19, a CD9 mAb, as well as the act-IgG, and bound to a 40 kD membrane protein. The inhi-IgG prevented the binding of IV-3, a mAb against Fc gamma receptor II (Fc gamma RII), but did not prevent the binding of NNKY 1-19 to its antigen. We suggest that the activating autoantibody recognized CD9 antigen and activated both the thromboxane- and phospholipase C-dependent pathways, while the inhibitory autoantibody recognized the Fc gamma RII and inhibited CD9 antibody-induced platelet activation mediated via this receptor.
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PMID:Platelet activation induced by an antiplatelet autoantibody against CD9 antigen and its inhibition by another autoantibody in immune thrombocytopenic purpura. 821 30

The recent reports of receptors for IgA on blood and mucosal phagocytes suggest a more active role then previously thought for IgA in host defense. Using a mAb and flow cytometry we determined the expression of the Fc alpha R on resting and chemoattractant-stimulated blood neutrophils and compared them with mucosal neutrophils. Fc alpha R expression on blood neutrophils could be rapidly up-regulated in vitro, increasing three to fourfold within minutes of exposure to the chemoattractants FMLP (optimal at 10(-8) M) and zymosan activated serum (a source of C5a). The level of Fc alpha R expression found on neutrophils obtained from bronchoalveolar lavage of cystic fibrosis patients with chronic lung infection was almost identical to that found on blood neutrophils from the same patients maximally activated in vitro. The rise in Fc alpha R expression induced by 10(-8) M FMLP was rapid, with a plateau in 15 to 20 min, and was not inhibited by 10 mg/ml of cycloheximide or puromycin, suggesting that the mechanism of up-regulation involves translocation from intracellular storage pools. Ionomycin (2 mM) plus 1.2 mM CaCl2 also increased expression of Fc alpha R, and its effects were inhibited by EDTA. Trifluoperazine, an inhibitor of calmodulin and/or protein kinase C-dependent processes, blocked the increase in Fc alpha R expression induced by FMLP, but the effects of the chemoattractant were not blocked by EDTA, suggesting that intracellular stores of calcium are important in the physiologic regulation of Fc alpha R expression. Neutrophil superoxide production could be induced by aggregated IgA, and was increased if the neutrophils were pretreated with FMLP, correlating with the increase in Fc alpha R expression. The superoxide response to a suboptimal dose of aggregated IgG was unaffected by FMLP pretreatment, and antibodies to Fc gamma R failed to block the superoxide production induced by IgA. Thus, the increase in phagocyte surface expression of Fc alpha R induced by chemoattractants in vitro and on mucosal cells in vivo, and the concomitant increase in IgA-mediated function may greatly facilitate the defense of mucosal surfaces.
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PMID:Increased Fc alpha R expression and IgA-mediated function on neutrophils induced by chemoattractants. 838 96

The transmembrane isoform of Fc gamma RIII, Fc gamma RIIIA, is found on NK cells, cultured monocytes, and tissue macrophages in association with a dimer of an accessory subunit, either gamma or zeta. Functions of individual Fc receptors have been difficult to analyze due to coexpression of the receptors on hematopoietic cells and permanent cell lines expressing Fc receptors. cDNAs for the alpha and gamma subunits of Fc gamma RIIIA were cotransfected into COS-1 cells, which lack endogenous Fc receptors, to evaluate receptor-mediated phagocytosis and changes in [Ca2+]i. Transfectants both bound and phagocytosed IgG-sensitized erythrocytes and, following activation of Fc gamma RIIIA, increased [Ca2+]i. The gamma subunit was essential both for the surface expression of the receptor and for transduction of the phagocytic signal. Truncation of the gamma subunit cytoplasmic domain (amino acids 65-80) eliminated phagocytic function. Phorbol ester inhibited phagocytosis in a concentration-dependent manner, but did not affect IgG-sensitized erythrocytes binding, suggesting that a protein kinase C-dependent pathway inhibits phagocytosis. The data indicate that a tyrosine containing cytoplasmic domain within the gamma subunit is required for phagocytosis by Fc gamma RIIIA.
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PMID:In the absence of other Fc receptors, Fc gamma RIIIA transmits a phagocytic signal that requires the cytoplasmic domain of its gamma subunit. 840 49

Human peripheral blood natural killer (NK) cells (CD56+, CD16+, CD3 epsilon- lymphocytes) express CD69 after their stimulation by interleukin-2 (IL-2) or interferon-alpha (IFN-alpha). This activation antigen represents a triggering surface molecule in NK cell clones as its stimulation triggers the cytolytic machinery of these cells. However, the mechanisms regulating the expression of CD69 in NK cells are unknown despite the functional relevance of CD69 in NK cell activation. Thus, we have analyzed the role of protein kinase C (PKC) and protein tyrosine kinases (PTK) in the expression of CD69 on purified NK cells activated by IL-2, IFN-alpha, anti Fc gamma RIII (CD16) monoclonal antibodies or by K562 target cells. We found that CD69 is induced on NK cells not only by IL-2 and IFN-alpha but also by activation of the CD16 pathway, the interaction with NK target cells and the direct activation of PKC by phorbol 12-myristate 13-acetate (PMA), indicating that CD69 induction is associated to different NK activation pathways. The treatment with the PKC inhibitor staurosporine abolished the induction of CD69 induced by PMA or K562. However, it did not significantly affect CD69 induction by IL-2, IFN-alpha or CD16 cross-linking. This demonstrates that whereas PKC can play a central role in the regulation of CD69 expression in some instances (response to K562 cells or PMA), it does not participate in others (response to IL-2, IFN-alpha or anti CD16 monoclonal antibodies). On the other hand genistein, a competitive inhibitor of PTK enzymes, blocked the expression of CD69 induced by activation of NK cells via IL-2 or IFN-alpha receptors, CD16 and K562 receptor(s), indicating that stimulation of PTK is a common step in the signal transduction events leading to the induction of CD69 antigens after the activation of NK cells via these receptors.
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PMID:Regulation of CD69 expression on human natural killer cells: differential involvement of protein kinase C and protein tyrosine kinases. 847

The lateral mobility of membrane proteins can reflect the extent of various protein-protein interactions. Using the fluorescence recovery after photobleaching technique, we have studied the lateral mobility of human Fc gamma RIIa and some Fc gamma RIIa mutants expressed in either P388D1 cells, a mouse macrophage-like cell line, or in Chinese hamster ovary (CHO) cells [1]. After treatment with phorbol myristate acetate (PMA), only the Fc gamma RIIa molecules capable of mediating rapid endocytosis of immune complexes exhibited a reduced lateral diffusion coefficient with respect to untreated controls. Wild type Fc gamma RIIa expressed in CHO cells, and nonfunctional Fc gamma RIIa mutants expressed in P388D1 cells did not show any differences upon PMA treatment. This finding suggests that protein kinase C activation evokes additional protein-protein interactions with the cytoplasmic domain of functional Fc gamma RIIa, which reduced receptor lateral mobility. The identity of these putative interacting proteins and the nature of the interactions remain to be elucidated.
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PMID:Lateral mobility of Fc gamma RIIa is reduced by protein kinase C activation. 852 72

Interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) are well known mediators in infectious processes with pleiotropic effects on a variety of cells. These cytokines are known to upregulate Fc receptor (Fc gamma R)-mediated phagocytosis by human polymorphonuclear neutrophils (PMN) but the mechanisms of this enhanced phagocytosis are not known. We investigated the effects of various alterations in intra- and extracellular events on cytokine-induced phagocytic upregulation. Blockade of mRNA synthesis, protein kinase C activation, or G protein activation prevented enhanced phagocytosis by either cytokine. The PMN phagocytic response to TNF-alpha, but not IL-1 beta, was also blunted by agents interfering with mRNA translation or Fc gamma R recycling.
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PMID:Cytokine-mediated human polymorphonuclear neutrophil phagocytosis: evidence of differential sensitivities to manipulation of intracellular mechanisms. 859 38

In this study, the extracellular ATP (ATPo)-induced biochemical events were elucidated by comparing them with either the Fc epsilon RI- or Fc gamma R-induced events in the mouse mast cell line MC9. The omission of extracellular Ca2+ almost completely abolished the elevation of intracellular Ca2+ ([Ca2+]i) in the ATPo-stimulated cells, but only suppressed the second phase of the increase of [Ca2+]i in FcR-stimulated cells, thus suggesting that the ATPo-induced elevation of [Ca2+]i is totally dependent on the entry of extracellular Ca2+. Pretreatment with genistein, which inhibits protein kinases, especially protein tyrosine kinase, inhibited the FcR-triggered increase of [Ca2+]i, but not the ATPo-triggered one; however, such pretreatment did suppress both ATPo- and FcR-mediated beta-hexosaminidase release. An immunoblot analysis revealed that both ATPo and the cross-linking of FcRs led to tyrosine phosphorylation of 44- and 110-kDa proteins, which thus suggested that these tyrosine-phosphorylated proteins are involved in a modulation of the degranulation process following an elevation of [Ca2+]i. Pretreatment with PMA inhibited the FcR-induced [Ca2+]i increase, while not inhibiting the ATPo-induced one, thus suggesting that ATPo can mobilize [Ca2+]i even when protein kinase C (PKC) has already been activated. Pretreatment of calphostin C, a specific PKC inhibitor, had little effect on the ATPo-mediated beta-hexosaminidase secretion, thus indicating that the ATPo-induced degranulation is not mediated by PKC. Taken together, these results demonstrate that ATPo activates MC9 mast cells by a mechanism that is different from the activation induced by the cross-linking of FcRs.
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PMID:Extracellular ATP activates mast cells via a mechanism that is different from the activation induced by the cross-linking of Fc receptors. 862 38

NNKY5-5, an IgG monoclonal antibody directed against the von Willebrand factor-binding domain of glycoprotein (GP) Ib alpha, induced weak but irreversible aggregation (or association) of platelets in citrate-anticoagulated platelet-rich plasma. This phenomenon was defined as small aggregate formation (SAF). Platelets in hirudin-anticoagulated plasma or washed platelets showed little response to NNKY5-5 alone, but the antibody potentiated aggregation induced by low concentrations of adenosine diphosphate or platelet-activating factor. NNKY5-5 did not induce granule release or intracellular Ca2+ mobilization. However, NNKY5-5 caused tyrosine phosphorylation of a 64-kD protein and activation of a tyrosine kinase, p72syk. An anti-Fc gamma II receptor antibody had no effect on SAF, suggesting that NNKY5-5 activated platelets by interacting with glycoprotein Ib. Fab' fragments of NNKY5-5 did not induce SAF, but potentiated aggregation induced by other agonists. The Fab' fragment of NNKY5-5 induced the activation of p72syk, suggesting that such activation was independent of the Fc gamma II receptor. Cross-linking of the receptor-bound Fab' fragment of NNKY5-5 with a secondary antibody induced SAF. GRGDS peptide, chelation of extracellular Ca2+, and an anti-GPIIb/IIIa antibody inhibited NNKY5-5-induced SAF, but had no effect on 64-kD protein tyrosine phosphorylation or p72syk activations. Various inhibitors, including aspirin and protein kinase C, had no effect on SAF, protein tyrosine phosphorylation, or p72syk activation. In contrast, tyrphostin 47, a potent tyrosine kinase inhibitor, inhibited NNKY5-5-induced SAF as well as tyrosine phosphorylation and p72syk activation. Our findings suggest that binding of NNKY5-5 to GPIb potentiates platelet aggregation by facilitating the interaction between fibrinogen and GPIIb/IIIa through a mechanism associated with p72syk activation and tyrosine phosphorylation of a 64-kD protein.
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PMID:Tyrosine phosphorylation and p72syk activation by an anti-glycoprotein Ib monoclonal antibody. 905 41

Co-clustering of Fc gamma RIIb and B-cell receptor (BCR) inhibits cell activation by interrupting BCR stimulated signal transduction. The immunoreceptor tyrosine-based inhibitory motif (ITIM) of Fc gamma RIIb becomes tyrosyl phosphorylated (P-ITIM) upon co-clustering with BCR then P-ITIM interacts with several signalling molecules, some of which negatively regulate the cell activation process. The molecules recruited by the P-ITIM of human Fc gamma RIIb have not been characterised yet. In order to affinity isolate the potential functional partner molecules of human Fc gamma RIIb, synthetic peptides were designed to cover almost the entire intracellular Fc gamma RIIb domain, including Fc gamma RIIb2 specific sequences and stretches containing the phosphorylated and non-phosphorylated ITIM. We report here that several tyrosyl phosphorylated proteins bind to the P-ITIM peptide from both resting and activated B-cell lysates, the 53-56 kDa being the most prominent one. A fraction of the 53-56 kDa bands were identified as the protein tyrosine kinase (PTK), Lyn which also bound to ITIM peptide, pointing to its role in initiating Fc gamma RIIb-mediated negative regulation. Among the P-ITIM associated tyr phosphorylated components, the 145 kDa one was identified as the inositol polyphosphate 5-phosphatase, SHIP and the 72 kDa protein as the protein tyrosine phosphatase (PTP) SHP2, whereas SHP1 was not detected. Phosphatase activity assays showed that P-ITIM bound about five times higher SHIP and four times higher PTP activity than the ITIM containing peptide. Furthermore, we detected PKC and MAPK in both ITIM and P-ITIM peptides precipitated samples. Since human B-cells express both Fc gamma RIIb1 and Fc gamma RIIb2, differing in a 19 amino acid insert in the cytoplasmic tail of the former, we investigated the components binding to Fc gamma RIIb1 and Fc gamma RIIb2 specific sequences. Synthetic peptide representing Fc gamma RIIb1 and Fc gamma RIIb2 specific sequences weakly bound unidentified tyr phosphorylated proteins at 50-56 kDa, while the insert itself did not bind a detectable amount of protein. Neither of the ITIM or P-ITIM bound molecules were observed in samples precipitated with peptides corresponding to Fc gamma RIIb1 or Fc gamma RIIb2 specific sequences. These observations suggest that protein kinases associate with both ITIM and P-ITIM of human Fc gamma RIIb, Lyn being responsible for the tyrosyl phosphorylation of ITIM. SHIP and SHP2 phosphatases selectively bind to the phosphorylated ITIM. Based on these data we assume that SHIP and SHP2 recruited in vivo to the Fc gamma RIIb co-clustered BCR are responsible for the Fc gamma RIIb mediated negative regulation of human B-cell activation.
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PMID:Fc gamma receptor type IIb induced recruitment of inositol and protein phosphatases to the signal transductory complex of human B-cell. 923 45

A chemiluminescence procedure has been developed to determine superoxide anion (O2-) generation and myeloperoxidase (MPO) release from human activated neutrophils. By using this procedure, the role of protein kinase C (PKC) and cytosolic calcium ion (Ca2+[i) for O2- generation and MPO release was examined. Activation of Fc gamma R on neutrophils with IgG-coated zymosan (IgGZ) caused a transient rise of Ca2+[i, followed by O2- generation and MPO release. A PKC inhibitor suppressed completely the O2- generation and slightly the MPO release. Direct activation of PKC by a specific PKC activator, phorbol myristate acetate (PMA), induced a remarkable O2- generation and a small MPO release, indicating that PKC may regulate entirely O2- synthesis and partially MPO degranulation. Influx of extracellular Ca2+ induced by the calcium ionophore A23187 provoked MPO release only. Complete inhibition of this MPO release with a Ca2+/calmodulin (CaM)-coupling inhibitor and a CaM inhibitor provides evidence that Ca2+[i may regulate MPO degranulation through direct activation of CaM, but not PKC. The Ca2+/CaM inhibitors significantly prevented IgGZ-induced O2- generation and MPO release, while they did not affect PMA-induced O2- generation and MPO release. These results suggest that in Fc gamma R-stimulated neutrophils, Ca2+[i activates CaM, which in turn mediates not only activation of PKC-induced O2- synthesis and MPO degranulation, but also MPO degranulation without PKC intermediate.
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PMID:The role of protein kinase C and [Ca2+]i in superoxide anion synthesis and myeloperoxidase degranulation of human neutrophils. 1065 91


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