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)

Engagement of MHC class II (Ia) molecules on B cells induces tyrosine phosphorylation, phosphoinositide turnover, elevation of intracellular calcium concentrations, and a rise in cAMP levels. However, a role for these biochemical signals in mediating functional responses induced by Ia ligands remains largely undefined. In this study, we utilized the induction of B cell adhesion by Ia ligands to demonstrate a role for signals transduced via Ia molecules in the generation of a functional response. Ia ligands that induced B cell aggregation induced tyrosine phosphorylation, whereas Ia ligands that did not induce B cell aggregation failed to induce any detectable tyrosine phosphorylation. Ia-induced B cell aggregation and tyrosine phosphorylation were inhibited by genistein and by herbimycin A, inhibitors of tyrosine kinases (PTK). Sphingosine and calphostin C, inhibitors of protein kinase C (PKC), also inhibited Ia-induced adhesion whereas HA1004, an inhibitor of cyclic nucleotide-dependent kinases, did not. Ia ligands induced both LFA-1-dependent and LFA-1-independent B cell adhesion. These two pathways of cell adhesion differed in their requirement for activation signals. PKC activation was sufficient for LFA-1-dependent adhesion, whereas LFA-1-independent adhesion required independent phosphorylation events mediated by PKC and by PTK. These results provide functional relevance for biochemical signals transduced via Ia molecules by demonstrating that Ia-induced B cell adhesion is mediated by the activation of PKC and by one or more PTK.
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PMID:Role of protein kinase activation in the induction of B cell adhesion by MHC class II ligands. 151 59

Recent attention has focused on the role keratinocytes (KC) may play in the induction of T cell-mediated inflammatory responses in skin, particularly because KC, when activated by immunologic stimuli, express MHC class II Ag and secrete immunomodulatory cytokines. We tested the capacity of normal human KC that were stimulated with PMA to induce PBMC proliferation. PMA-treated, but not untreated, KC induced proliferation of allogeneic as well as autologous PBMC; in addition, when purified CD4+ or CD8+ T cells were used as responders, each subset proliferated. PBMC proliferation was not due to direct action of PMA on PBMC, nor to contamination of KC cultures with Langerhans cells (LC) or dermal APC. Pretreatment with different protein kinase C inhibitors abrogated the capacity of PMA-stimulated KC to induce proliferation. Paraformaldehyde-fixed PMA-KC stimulated PBMC proliferation, whereas supernatants from PMA-treated KC failed to do so, indicating that a membrane-associated activity on PMA-KC contributes to the induction of PBMC proliferation. PMA induced intercellular adhesion molecule-1 (ICAM-1) expression on KC; furthermore, mAb against ICAM-1 or against its ligand lymphocyte function-associated Ag (LFA-1) (CD11a/CD18) significantly, but incompletely, reduced the stimulatory capacity of PMA-treated KC, indicating that ICAM-1/LFA-1 interaction contributed to PBMC proliferation. IFN-gamma or TNF-alpha also induced ICAM-1 on KC, but these KC failed to stimulate proliferation, suggesting that PMA induces additional signals from KC, which act in concert with ICAM-1 to promote proliferation. Finally, mAb against HLA-ABC or HLA-DR did not inhibit proliferation. We conclude that PMA can activate KC to stimulate T cell proliferation in a MHC-independent fashion. This activation is mediated by protein kinase C and in part by the induction of ICAM-1 expression on KC.
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PMID:Phorbol myristate acetate-activated keratinocytes stimulate proliferation of resting peripheral blood mononuclear lymphocytes via a MHC-independent, but protein kinase C- and intercellular adhesion molecule-1-dependent, mechanism. 167 Sep 43

We recently showed that synthetic lipopeptides, analogues of the N-terminal region of bacterial lipoprotein, induce DNA synthesis in B lymphocytes in the absence of enhanced phosphatidylinositol 4,5-bisphosphate hydrolysis and protein kinase C translocation. Here we demonstrate that lipopeptides are capable of inducing enhanced expression of MHC class II molecules and early increases in the intracellular free calcium concentration ([Ca2+]i) in B cells. However, they do not effect T cells. The increase in [Ca2+]i seen in B cells is due primarily to Ca2+ release from intracellular stores. Since lipopeptides differ in their capability to induce early increases in [Ca2+]i and since the calcium response does not correlate with the ability of lipopeptides to induce proliferation and expression of MHC class II molecules, we suggest that this biochemical event may not be essential for lipopeptide-mediated B-cell activation.
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PMID:Increase in the intracellular free calcium concentration is not an obligatory early event in lipopeptide-induced B-cell activation. 187 81

The inability of CD4+ T cells of HIV-1-infected patients to mount an effective immune response is widely believed to explain the increased susceptibility of these patients to opportunistic infections. Although the full explanation for T-cell dysfunction in HIV-1 infection is not yet understood, at least two fundamentally distinct mechanisms are thought to contribute: depletion of CD4+ T cells and qualitative CD4+ T-cell dysfunction independent of T-cell depletion. Many HIV-1-infected patients manifest reduced T-cell responses to recall antigens prior to measurable CD4+ T-cell depletion, and among the proposed explanations for this phenomenon are gp120-mediated interference with T-cell activation by way of inhibition of CD4-class II major histocompatibility complex (MHC) determinant interactions, gp41-mediated inhibition of protein kinase C-dependent T-cell activation, formation of gp41 cross-reactive antibodies that react with MHC class II determinants, transforming growth factor-beta (TGF-beta)-mediated immunosuppression, and decreased functions of antigen-presenting and antigen-processing cells (macrophages and bone marrow-derived dendritic cells). Despite their detection in most HIV-1-infected patients, these qualitative T-cell defects do not herald the onset of life-threatening disease. The appearance of severe clinical manifestations of AIDS, particularly opportunistic infections, occurs primarily in patients whose CD4+ T-cell count is significantly reduced. Depletion of CD4+ T cells may be a direct consequence of HIV-1 infection that occurs as a result of syncytia formation, autoantibody-mediated cytolysis, gp120-specific antibody-dependent cytolysis, and/or gp120-specific T-cell mediated cytolysis. The thymus is severely affected in patients with late-stage disease, and although there is no proof that the failure of the thymus to regenerate new T cells contributes to T-cell depletion in patients with AIDS, the likelihood seems high that this is the case. Indeed, if prolonged suppression of HIV-1 replication can be achieved with newer anti-HIV drugs or combinations of drugs, reconstitution of a normal immune system seems likely, provided that the capacity to regenerate T cells has not been irrevocably lost as a consequence of viral infection. In summary, available evidence indicates that HIV-1 uses a complex array of mechanisms to disrupt T-cell mediated immunity, but because most of these involve a direct role for HIV-1 proteins, such mechanisms are likely to be reversible if suppression of HIV-1 replication can be achieved.
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PMID:Impaired immunity in AIDS. The mechanisms responsible and their potential reversal by antiviral therapy. 198 24

These studies examined the role of the MHC class II Ag in signal transduction using human B lymphocytes. Early events in signal transduction were considered including the intracellular calcium [Ca2+)i) flux, the activation of phospholipase C, and induction of protein phosphorylation. The (Ca2+)i was enhanced after incubation of B lymphocytes with several mAb anti-HLA class II and cross-linking with rabbit anti-mouse-F(ab')2. We have also demonstrated an enhancement of the (Ca2+)i in response to a suboptimal concentration of a monoclonal anti-IgM either in the presence of or after preincubation with a mAb anti-HLA class II. The activation of phospholipase C was assessed by measuring the generation of inositol phosphates in permeabilized B lymphocytes. mAb anti-HLA-class II of two different epitopes were used to demonstrate both the (Ca2+)i flux and the generation of inositol phosphates. Two-dimensional gel electrophoresis was used to investigate the phosphorylation pattern of resting B lymphocytes and the changes in the pattern after stimulation with soluble mAb anti-HLA-DR, immobilized mAb anti-HLA-DR, and PMA. In addition to the augmentation of phosphorylation observed with regard to phosphoproteins already present in resting B lymphocytes, new phosphorylations were observed after stimulation by any one of the reagents. Furthermore, stimulation by PMA did not result in an identical pattern to that observed after stimulation by mAb anti-HLA class II. An inhibition of the proliferative response to PMA was demonstrated after prestimulation of cells with immobilized mAb anti-HLA-DR, supporting the notion of a shared pathway of activation. In summary, these data demonstrate signal transduction via MHC class II Ag as assessed by three different measures of early events in human B lymphocyte activation and suggest that a protein kinase C pathway is at least partly involved.
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PMID:Early biochemical events after MHC class II-mediated signaling on human B lymphocytes. 239 73

We have demonstrated that IFN-gamma, a potent peptide mediator in inflammatory responses, operates via the protein kinase C dependent transduction pathway in the induction of class II MHC antigens on rat microvascular endothelial cells. Stimulators of protein kinase C, like PMA, replaced IFN-gamma in the induction of MHC class II on endothelial cells in a dose-dependent manner. Selective enzyme inhibitors of protein kinase C, H-7 as well as sphingosine down-regulated the IFN-gamma induced class II expression in a dose-dependent manner. Addition of cAMP or cGMP in the culture, had no effect on the class II expression on the endothelial cells. Transient rise of cytosolic Ca2+ by calcium ionophore A23187, or a calmodulin antagonist W-7, had no effect on the IFN-gamma induced class II expression.
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PMID:Protein kinase C is crucial in signal transduction during IFN-gamma induction in endothelial cells. 254 4

Membranes were isolated from B cells stimulated with phorbol 12-myristate 13-acetate (PMA) for a time sufficient to allow maximal redistribution and activation of protein kinase C (PKC). Exposure of such membranes to a short incubation with [gamma-32P]ATP resulted in the detection of at least nine unique or hyperphosphorylated membrane proteins by SDS-PAGE and autoradiography. The appearance of these phosphoproteins was blocked by pretreatment of the membranes with H-7 or sangivamycin, two selective inhibitors of PKC. In addition, membranes purified from B cells treated with an inactive phorbol ester or stimulated with dibutyryl cAMP failed to exhibit a pattern of new phosphoproteins. These results are consistent with the involvement of PKC in the phosphorylation of the proteins. These phosphoproteins are also candidates for proteins whose functions are modified as a consequence of early signal delivery to resting B cells following membrane immunoglobulin occupancy. This system was utilized to identify the heavy chain of MHC class I molecules as one of the membrane proteins phosphorylated by PKC. The MHC class II molecules were not phosphorylated in membranes isolated from PMA-treated normal B cells or from PMA-treated B cells which had previously been exposed to IL-4. These results indicate that class I, but not class II, MHC molecules are phosphorylated by PKC. It is possible that such a modification of cell surface class I molecules may be involved during the process of signal transduction leading to B cell activation.
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PMID:Phosphorylation of class I but not class II MHC molecules by membrane-localized protein kinase C. 263 45

Cell surface expression of CD4, an invariant membrane glycoprotein, is characteristic of the MHC class II-restricted T cell helper/inducer subset. Although the specificity and restriction patterns of T lymphocytes are determined by the T cell receptor for antigen, CD4 might represent an additional "interaction" molecule that is required to strengthen the interaction between T cells, antigen, and antigen-presenting cells. In this manuscript, we have shown that the cell surface expression of CD4 is correlated with activation of T cells. Data presented in this paper have demonstrated, for the first time, that antigenic stimulation of human T cell clones caused a decrease in the expression of the CD4 marker (as well as to the CD3 marker) to about 50% of the constitutive level. As previously demonstrated, PMA caused modulation of CD4 and CD3, which suggested that phosphorylation by protein kinase C played a crucial role in the regulation of the expression of both markers. The parallel down-regulation of CD3 and CD4 after antigen stimulation suggested that both markers might be members of a multimolecular complex mediating T cell activation.
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PMID:Modulation of CD4 by antigenic activation. 310 Jun 38

The membrane glycoproteins CD4 (L3T4) and CD8 (Lyt2) are expressed on distinct populations of mature murine T lymphocytes, and are thought to be receptors for monomorphic determinants expressed on MHC class II and class I molecules, respectively. Although they differ in their ligand specificity, it has been presumed that CD4 and CD8 perform equivalent functions in the T cells that bear them. Since activation of protein kinase C (PKC) is known to cause rapid down-regulation of various receptors, including the T cell receptor complex (TcR complex), we treated cells with phorbol 12-myristate 13-acetate (PMA), a PKC activator, to determine whether cell-surface expression of CD4 and CD8 would be similarly affected by this intracellular mediator. Brief or relatively prolonged treatment with PMA induced mature murine T cells to reduce their surface expression of the TcR complex and of CD4, but not of CD8. Similarly, PMA rapidly induced transfected L cells to down-regulate surface CD4 expression, but had no effect on surface CD8 expression. Most significantly, PMA treatment induced CD4+CD8+ immature thymocytes to rapidly reduce their surface CD4 expression, but, again, it had no immediate effect on the surface expression of CD8. These results indicate that CD4 and TcR complex cell-surface expression are both sensitive to PKC activation by brief treatment with PMA, whereas CD8 expression is not, and suggest that CD4 and CD8 surface expression levels are regulated by distinct intracellular mechanisms.
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PMID:Nonequivalent effects of PKC activation by PMA on murine CD4 and CD8 cell-surface expression. 326

gp39 is expressed on anti-CD3-activated Th, and binds CD40 on the B cell, driving B cell cycle entry. In this study, the signal-transduction pathway initiated in B cells as a consequence of interacting with activated Th is examined. Unlike anti-membrane Ig (anti-mlg) or anti-MHC class II, plasma membranes (PM) isolated from anti-CD3-activated Th, PMAct did not trigger an increase in the B cell intracellular concentrations of cAMP or calcium. In addition, PMAct did not stimulate protein kinase C activation as measured by myristoylated alanine-rich C-kinase substrate (MARCKS) phosphorylation and protein kinase C translocation. The failure to detect these biochemical events may be caused by the asynchrony with which PMAct induce these normally transient biochemical changes. Alternatively, PMAct may not trigger these events. PMAct did induce the tyrosine phosphorylation of several B cell substrates. Neutralizing Abs directed against gp39 inhibited PMAct-induced protein tyrosine phosphorylation of B cell substrates. These results suggest that cognate interactions in B cells initiate a signal-transduction pathway that is different from the pathway initiated by cross-linking of mlg or MHC class II.
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PMID:Signaling events during helper T cell-dependent B cell activation. I. Analysis of the signal transduction pathways triggered by activated helper T cell in resting B cells. 751 24


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