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)

Costimulation of the T cell receptor (TCR) and CD28 is required for optimal interleukin-2 (IL-2) induction. These signals, which can be replaced by the pharmacological agents phorbol ester (PMA) and Ca2+ ionophore, synergistically activate the mitogen-activated protein kinase (MAPK) JNK. Cyclosporin A, an inhibitor of the Ca2+-dependent phosphatase calcineurin which blocks IL-2 induction, abrogates Ca2+-triggered synergistic JNK activation. As protein kinase C (PKC) downregulation inhibits PMA+ionophore-induced JNK activation, we examined whether a particular PKC isoform is preferentially involved in this response. We found that PKC-theta but neither PKC-alpha nor PKC-epsilon participates in JNK activation, whereas all three PKCs lead to ERK MAPK activation. PKC-theta specifically cooperates with calcineurin, and together their signals converge on (or upstream of) Rac leading to potent JNK activation. Similarly, calcineurin and PKC-theta specifically synergize to induce transcription of reporters driven by the c-jun and IL-2 promoters. PKC-theta and calcineurin are also partially responsible for the synergistic activation of JNK following TCR and CD28 ligation. Preferential cooperation between PKC-theta and calcineurin is observed in Jurkat T cells but not in HeLa cells. These results indicate that PKC isozymes have distinct biological functions and suggest that synergistic JNK activation is an important function for PKC-theta in T-cell activation.
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PMID:Calcineurin preferentially synergizes with PKC-theta to activate JNK and IL-2 promoter in T lymphocytes. 960 92

In the present study, we showed that simultaneous ligation of the monoclonal antibodies (mAb) against CD6 and CD28 induces T-cell proliferation in purified resting T lymphocytes in the absence of T-cell receptor (TCR) occupancy. No cell proliferation was observed when the mAb were cross-linked alone or used simultaneously in the soluble form. T-cell proliferation mediated through CD6/CD28 is accompanied by the up-regulation of interleukin-2 (IL-2) mRNA and expression of IL-2 receptors on the cell surface. In the presence of IL-2-neutralizing mAb the proliferative response of the T cell induced through CD6/CD28 was inhibited dose dependently. Cross-linking mAb to CD6 and CD28 alone or together did not down-regulate the CD3/TCR complex. T-cell proliferation mediated through CD6/CD28 was only partially blocked by the immunosuppressive drug, cyclosporin A (CsA), whereas anti-CD28-induced T-cell proliferation in the presence of the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), was unaffected. In sharp contrast T-cell proliferation mediated by anti-CD6 in the presence of TPA was efficiently blocked by CsA. In addition, two protein kinase C (PKC) inhibitors, GF 109203X and H-7 dose-dependently inhibited T-cell proliferation mediated through CD6/CD28, suggesting that PKC activation may be involved. Furthermore, there was a marked differential dose-dependent inhibitory effect of the PKC inhibitors on T-cell proliferation mediated by the co-ligation of anti-CD6 or anti-CD28 in the presence of anti-CD3, with the former being more sensitive to PKC inhibition. Taken collectively, our results suggest that T-cell activation can occur through an antigen-independent pathway by cross-linking the accessory molecules, CD6 and CD28, and that these two cell surface antigens may have distinct signalling pathways.
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PMID:Simultaneous cross-linking of CD6 and CD28 induces cell proliferation in resting T cells. 964 Feb 46

Ligation of CD28 molecules expressed on the surface of human leukaemic natural killer-like YT cells triggers intracellular signals leading to cytolysis of target cells expressing CD80 or CD86 molecules. Known intracellular events include tyrosine phosphorylation, activation of phosphatidylinositol 3-kinase, and protein kinase C (PKC). In this study, we report that PKC-delta isoenzyme activity is required for CD28-triggered cytotoxicity mediated by YT cells and we also demonstrate that one of the primary targets of bryostatin 1, a modulator of PKC activity, is PKC-delta. Treatment of YT cells with bryostatin 1 caused degradation of PKC-delta, but not other PKC isoenzymes, and completely blocked the cytolytic activity of YT cells. In addition, PKC-delta-specific antibody introduced into YT cells by electroporation inhibited partially the YT cell-mediated cytotoxicity of B-lymphoblastoid cell line JY. This effect was specific, since addition of anti-PKC-delta antibody-blocking peptide in combination with anti-PKC-delta antibody to YT cells for electroporation, neutralized the effect of this antibody. These results demonstrate that YT cell cytolytic activity is dependent on PKC-delta, which is selectively down-regulated by bryostatin 1.
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PMID:Involvement of protein kinase C-delta in CD28-triggered cytotoxicity mediated by a human leukaemic cell line YT. 976 47

CD3, CD2, and CD28 are functionally distinct receptors on T lymphocytes. Engagement of any of these receptors induces the rapid tyrosine phosphorylation of a shared group of intracellular signaling proteins, including Vav, Cbl, p85 phosphoinositide 3-kinase, and the Src family kinases Lck and Fyn. Ligation of CD3 also induces the tyrosine phosphorylation of HS1, a 75-kDa hematopoietic cell-specific intracellular signaling protein of unknown function. We have examined changes in HS1 phosphorylation after differential stimulation of CD3, CD2, and CD28 to elucidate its role in T cells and to further delineate the signaling pathways recruited by these receptors. Unlike ligation of CD3, stimulation with anti-CD28 mAb or CHO cells expressing the CD28 ligands CD80 or CD86 did not lead to tyrosine phosphorylation of HS1 in Jurkat T cells. Additionally, no tyrosine phosphorylation of HS1 was induced by mitogenic pairs of anti-CD2 mAbs capable of activating the transcription factor NFAT (nuclear factor of activated T cells). Costimulation through CD28 and/or CD2 did not modulate the CD3-dependent phosphorylation of HS1. In vivo studies indicated that CD3-induced HSI phosphorylation was dependent upon both the Src family tyrosine kinase Lck and the tyrosine phosphatase CD45, did not require MEK1 kinase activity, and was regulated by protein kinase C activation. Thus, although CD3, CD28, and CD2 activate many of the same signaling molecules, they differed in their capacity to induce the tyrosine phosphorylation of HSI. Furthermore, activation-dependent tyrosine phosphorylation of HS1 was not required for NFAT transcriptional activation.
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PMID:Uncoupling activation-dependent HS1 phosphorylation from nuclear factor of activated T cells transcriptional activation in Jurkat T cells: differential signaling through CD3 and the costimulatory receptors CD2 and CD28. 979 75

The protooncogene Vav functions as a GDP/GTP exchange factor (GEF) for Rho-like small GTPases involved in cytoskeletal reorganization and cytokine production in T cells. Gene-targeted mice lacking Vav have a severe defect in positive and negative selection of T cell antigen receptor transgenic thymocytes in vivo, and vav-/- thymocytes are completely resistant to peptide-specific and anti-CD3/anti-CD28-mediated apoptosis. Vav acts upstream of mitochondrial pore opening and caspase activation. Biochemically, Vav regulates peptide-specific Ca2+ mobilization and actin polymerization. Peptide-specific cell death was blocked both by cytochalasin D inhibition of actin polymerization and by inhibition of protein kinase C (PKC). Activation of PKC with phorbol ester restored peptide-specific apoptosis in vav-/- thymocytes. Vav was found to bind constitutively to PKC-theta in thymocytes. Our results indicate that peptide-triggered thymocyte apoptosis is mediated via Vav activation, changes in the actin cytoskeleton, and subsequent activation of a PKC isoform.
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PMID:Vav regulates peptide-specific apoptosis in thymocytes. 984 24

Human placental protein 14 (PP14, also referred to as glycodelin and progesterone-associated endometrial protein) inhibits phytohemagglutinin (PHA)-stimulated T-cell proliferation and monokine secretion within PBMC populations. However, the mechanisms underlying these and other PP14 immunoinhibitory activities remain unclear. In the present study, we asked whether PP14's T-cell inhibitory effect is a direct one or, alternatively, an indirect consequence of accessory cell (AC) perturbation. Using either immunopurified PP14 or first-trimester amniotic fluid (AF) as a rich source of PP14, we documented inhibition of the proliferation of highly purified peripheral blood T-cells when stimulated with anti-CD3 mAbs or PHA in the presence of paraformaldehyde-fixed AC. Significantly, PP14 inhibited T-cell proliferation and IL-2 secretion induced by immobilized anti-CD3 and anti-CD28 mAbs in the absence of AC. PP14 depletion (via immunoprecipitation) abrogated AF's T-cell inhibitory activity, indicating that the PP14 within the amniotic fluid is required for this immunoregulatory effect. These findings establish that PP14 can inhibit T-cell proliferation in the absence of AC and thus add PP14 to the relatively restricted set of immunoinhibitory proteins that are known to target T-cells directly. Additional data demonstrate that PP14's inhibitory effect can be overridden by stimuli which circumvent early events during T-cell receptor (TCR) activation, namely, protein kinase C activators in combination with Ca2+ ionophores. These latter results suggest that PP14 inhibits early events in the TCR signaling pathway.
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PMID:Placental protein 14 functions as a direct T-cell inhibitor. 991 84

The induction of clonal anergy in a T cell inhibits IL-2 secretion because of the development of a proximal signal transduction defect. Fusion of anergic murine T cells to human Jurkat T leukemia cells and formation of heterokaryons failed to result in a complementation of this signaling defect and restoration of murine IL-2 mRNA inducibility. Instead, signal transduction to the human IL-2 gene became disrupted. Heterokaryons formed by the fusion of anergic murine T cells to normal murine T cells also failed to accumulate intracellular IL-2 protein in response to stimulation either with the combination of CD3 and CD28 mAbs or with ionomycin plus a protein kinase C-activating phorbol ester. The results argue against a loss-of-function signaling defect as the sole basis for clonal anergy induction and document the presence of a dominant-acting repressor molecule that inhibits signal transduction to the IL-2 gene within viable anergic T cells.
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PMID:Evidence for repression of IL-2 gene activation in anergic T cells. 997 2

Protein tyrosine kinases are critical for the function of CD28 in T cells. We examined whether the tyrosine kinases Pyk2 and Fak (members of the focal adhesion kinase family) are involved in CD28 signaling. We found that ligating CD28 in Jurkat T cells rapidly increases the tyrosine phosphorylation of Pyk2 but not of Fak. Paxillin, a substrate for Pyk2 and Fak, was not tyrosine-phosphorylated after CD28 ligation. CD28-induced tyrosine phosphorylation of Pyk2 was markedly reduced in the absence of external Ca2+. Previous studies have shown that the T cell antigen receptor (TCR) induces tyrosine phosphorylation of Pyk2. In this report, the concurrent ligation of CD28 and TCR increased tyrosine phosphorylation of Pyk2; however, the extent of phosphorylation by both receptors was equivalent to the sum of that induced by each receptor alone. The Syk/Zap inhibitor piceatannol blocked CD28, and TCR induced tyrosine phosphorylation of Pyk2, suggesting that Syk/Zap is involved in Pyk2 phosphorylation. In contrast, the phosphatidylinositol 3-kinase inhibitor wortmannin blocked TCR- but not CD28-induced phosphorylation of Pyk2, suggesting that CD28 and TCR activate distinct pathways to induce tyrosine phosphorylation of Pyk2. Notably, depleting phorbol 12-myristate 13-acetate-sensitive protein kinase C did not block CD28- and CD3-induced tyrosine phosphorylation of Pyk2. These data provide evidence for the involvement of Pyk2 in the CD28 signaling cascade and suggest that neither Fak nor paxillin is involved in the signaling pathways of CD28.
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PMID:CD28 ligation induces tyrosine phosphorylation of Pyk2 but not Fak in Jurkat T cells. 1003 72

CD40L expression is well recognized to be of critical importance in initiation of the immune response. Because cAMP mediates actions of bronchodilators commonly used in asthma, the effects of cAMP in regulating the immune response are of major importance. Cyclic AMP was found to either inhibit or markedly increase CD40L expression dependent upon the mechanisms of T cell activation. Cyclic AMP inhibited CD40L expression induced by TCR activation. In contrast, cAMP enhanced CD40L induced by CD2-mediated T cell activation or by calcium-dependent mechanisms. While neither CD28 costimulation nor exogenous IL-2 or IL-4 prevented cAMP inhibition in TCR activated cells, addition of calcium ionophore to TCR activation prevented any inhibitory effects and caused cAMP to increase CD40L expression. Actions of cAMP to increase CD40L expression appeared independent of PKC and were not a reflection of generalized cellular activation since neither CD25 nor CD69 expression was affected. The markedly contrasting actions of cAMP to decrease or increase CD40L expression, an important control point in the immune response, could be relevant to actions of commonly used medications including bronchodilators.
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PMID:Regulation of CD40L expression by cyclic AMP: contrasting proinflammatory and inhibitory actions. 1008 89

TRAIL (TNF-related apoptosis inducing ligand), like other members of the TNF family of proteins, is able to induce apoptosis in sensitive target cells. Recently, cell-surface TRAIL has been shown to be expressed by activated human and mouse T lymphocytes, raising the possibility that TRAIL might be involved in T cell-mediated cytotoxicity and/or immune regulation. In the present study we show by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis that activated, but not resting, mouse T cells express abundant TRAIL mRNA. TRAIL transcripts were detectable within 4 h of T cell activation. A panel of pharmacologic inhibitors was used to investigate the signal transduction pathways involved in TRAIL gene induction following T lymphocyte activation. TRAIL gene expression was sensitive to the src-like protein tyrosine kinase (PTK) inhibitor herbimycin A, as well as the more general PTK inhibitor genistein, suggesting the involvement of a src family PTK. The PKC inhibitors staurosporine and calphostin C, and the phosphatidylinositol 3-kinase (PI3-K) inhibitors wortmannin and LY294002, also prevented TRAIL mRNA transcription by activated T cells, indicating a role for PKC and PI3-K. In addition, TRAIL induction was inhibited by cyclosporin A, implicating the Ca(2+)/calmodulin-dependent protein phosphatase calcineurin. TRAIL expression was also blocked by rapamycin, which inhibits p70 S6 kinase involved in CD28 and interleukin (IL)-2 receptor signaling. However, TRAIL mRNA expression was not induced by IL-2, suggesting that TRAIL gene induction is not coupled to the IL-2 receptor. Data obtained by RT-PCR were confirmed at the protein level by immunoblotting with TRAIL-specific antibody. We conclude that TRAIL gene induction is initiated through a T cell receptor-associated signaling pathway similar to that responsible for the expression of cytokine genes such as IL-2.
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PMID:Murine TRAIL (TNF-related apoptosis inducing ligand) expression induced by T cell activation is blocked by rapamycin, cyclosporin A, and inhibitors of phosphatidylinositol 3-kinase, protein kinase C, and protein tyrosine kinases: evidence for TRAIL induction via the T cell receptor signaling pathway. 1050 2


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