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)

In this report, the co-stimulatory signals provided by CD80 (B7-1) or CD86 (B7-2) were compared to CD28 ligation by mAb. We demonstrate that while both anti-CD3 and anti-CD28 antibodies induced activation of phosphoinositide (PI) 3-kinase, the kinetics of activation differed. Anti-CD28 produced a sustained activation of PI 3-kinase while anti-CD3 induced activation was transient. Both B7-1 and B7-2 could induce prolonged activation of PI 3-kinase. The co-stimulatory effects of B7-1 and B7-2 were dependent on CD28 cross-linking, based on complete inhibition of PI 3-kinase activation by CD28 antibody Fab fragments. While Jurkat T cells co-stimulated with anti-CD3 and B7-1 or B7-2 secreted high levels of IL-2, there were distinct effects of anti-CD28 mAb and B7-1 or B7-2 on IL-2 secretion in conjunction with protein kinase C activation. To assess functional effects of CD28 ligation, pharmacologic inhibitors of PI 3-kinase were evaluated. In Jurkat cells, efficient inhibition of PI 3-kinase activation after B7-2 stimulation was achieved using wortmannin; however, we observed a surprising increase in IL-2 secretion after B7 or anti-CD28 stimulation. The effect of wortmannin was concentration dependent. Moreover, the effect was specific for receptor-mediated activation as wortmannin did not enhance phorbol ester plus ionomycin-induced IL-2 secretion. Another inhibitor of PI 3-kinase, LY294002, also resulted in augmentation of anti-CD28-induced IL-2 secretion by Jurkat cells. The effects of wortmannin on IL-2 secretion were also examined in primary T cells. In marked contrast, wortmannin resulted in a potent inhibition of anti-CD3 plus B7-1 or anti-CD28-induced IL-2 secretion while phorbol ester plus ionomycin-induced IL-2 secretion was wortmannin resistant. Together these observations demonstrate that signal transduction by both B7-1 and B7-2 involves PI 3-kinase, and that PI 3-kinase or other wortmannin-sensitive targets are important for IL-2 secretion. Finally, treatment of Jurkat cells with PI 3-kinase inhibitors alone was sufficient to induce low levels of IL-2 secretion. This is consistent with the notion that a wortmannin-sensitive target such as PI 3-kinase may down-regulate IL-2 secretion in Jurkat cells.
 ...
PMID:Both CD28 ligands CD80 (B7-1) and CD86 (B7-2) activate phosphatidylinositol 3-kinase, and wortmannin reveals heterogeneity in the regulation of T cell IL-2 secretion. 757 4

The present study compares the mitogen-activated protein (MAP) kinase responses in T cells activated with the CD28 ligands B7-1 (CD80) and B7-2/B70 (CD86). Ligands B7-1 and B7-2 do not activate the Raf-1/ERK2 cascade, but share the ability to activate related Jun kinases. These natural ligands for CD28 had no stimulatory effect alone on Jun kinase activation, but the data show that B7-1 and B7-2 could both co-operate with intracellular Ca2+ increase and protein kinase C (PKC) activation to stimulate Jun kinases. The present study shows that the interaction of CD28 with its ligands B7-1 and B7-2 can induce identical signal transduction through the MAP kinase cascades.
 ...
PMID:CD28 signal transduction pathways. A comparison of B7-1 and B7-2 regulation of the map kinases: ERK2 and Jun kinases. 860 25

The human leukemic cell line YT displays spontaneous cytotoxicity against CD80+ and/or CD86+ and ICAM-1+ target cells. In this work, we report that CD28-mediated cytotoxicity of YT involves tyrosine phosphorylation and activation of phosphatidylinositol (PI) 3-kinase, the Tec kinase Itk/Emt, and protein kinase C (PKC). YT mediates lysis of CD80+/CD86+ B lymphoblastoid cell lines and the murine mastocytoma p815 transfected with CD80 or CD86. The lysis was inhibited by two different Pi 3-kinase inhibitors, wortmannin and LY294002. The PKC inhibitors calphostin C and bisindolylmaleimide GF109203X also abolished YT-mediated cytotoxicity. Furthermore, exocytosis of cytolytic effector molecules was also inhibited by PI 3-kinase inhibitors and PKC inhibitors. PMA together with Ionomycin did not induce granule exocytosis or cytotoxicity by YT cells. Treatment of YT cells with PMA for up to 20 h, which depleted PMA-responsive PKC isoforms, had no effect on the CD28-mediated cytotoxicity. This cytotoxicity displayed by PMA-treated YT cells, however, could still be inhibited by Pi 3-kinase inhibitors and PKC inhibitors. Taken together, these results are consistent with a model in which activation of CD28 and LFA-1 induces tyrosine phosphorylation of the CD28 cytoplasmic domain, recruitment and activation of PI 3-kinase, as well as the Tec kinase Itk/Emt, and the activation of PMA-nonresponsive PKC isoenzymes. Activation of PI 3-kinase and PMA-nonresponsive PKC isoenzymes is shown to be involved directly in cytolytic granule release by YT cells.
 ...
PMID:CD28-mediated cytotoxicity by the human leukemic NK cell line YT involves tyrosine phosphorylation, activation of phosphatidylinositol 3-kinase, and protein kinase C. 861 44

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.
 ...
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.
 ...
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

Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a receptor present on T cells that plays a critical role in the downregulation of antigen-activated immune responses. CTLA-4 interacts with the ligands CD80 and CD86 on antigen-presenting cells (APC), and also directs the assembly of inhibitory signalling complexes that lead to quiescence or anergy. In this study, we show that human monocytes constitutively express CTLA-4. About 3% of monocytes expressed CTLA-4 on the cell surface, whereas the intracellular expression was higher and present in about 20% of the monocytes. The sequences of the cDNAs from human monocytes were identical to the sequences of CTLA-4 from T cells. Expression of CTLA-4 was also confirmed in the activated myelomonocytic cell lines U937 and THP-1. Monocytes, but not T cells, activated by interferon (IFN)-gamma also secreted soluble CTLA-4 in vitro. The CTLA-4 expression was upregulated upon treatment with phorbol 12-myristate 13-acetate (PMA) and IFN-gamma. This increased expression could be partially abolished by staurosporine, an inhibitor of protein kinase C (PKC). Ligation of CTLA-4 in the monocyte-like cell-line U937 with antibodies against CTLA-4 partially inhibited the proliferation of cells and the upregulation of cell-surface markers CD86, CD54, HLA-DR and HLA-DQ induced by IFN-gamma and Staphylococcus aureus, Cowan I strain (SAC). Ligation of CTLA-4 suppressed the PMA-stimulated activation of transcription activator protein 1 (AP-1) and nuclear factor (NF)-kappaB in the U937 cell line, indicating the involvement of an inhibitory signal transduction. These data provide the first evidence that CTLA-4 is constitutively expressed by monocytes and thus might be important for the regulation of immune mechanisms associated with monocytes.
 ...
PMID:Expression of CTLA-4 by human monocytes. 1184 92

The costimulatory molecule B7-2 (CD86) is expressed on the surface of APCs, including B cells. Considering the importance of B7-2 in regulating both T and B cell function, it may be important to understand the regulatory mechanisms governing its expression. We report in this study that stimulation of the B cell receptor (BCR) and/or a neurotransmitter receptor, the beta(2)-adrenergic receptor (beta(2)AR), may cooperate to regulate B cell-associated B7-2 expression in vitro and in vivo. beta(2)AR stimulation further enhanced the level of BCR-induced B7-2 expression in B cells potentially via protein tyrosine kinase-, protein kinase A-, protein kinase C-, and mitogen-activated protein kinase-dependent mechanisms. Importantly, BCR and/or beta(2)AR stimulation, but not histone hyperacetylation and DNA hypomethylation alone, increased B cell-associated B7-2 expression by increasing B7-2 mRNA stability, NF-kappa B nuclear binding, and NF-kappa B-dependent gene transcription. Thus, this study provides additional insight into the signaling intermediates and molecular mechanisms by which stimulation of the BCR and beta(2)AR may regulate B cell-associated B7-2 expression.
 ...
PMID:B cell receptor- and beta 2-adrenergic receptor-induced regulation of B7-2 (CD86) expression in B cells. 1205 47

CD80 and CD86, expressed on the antigen-presenting cells (APCs) provide costimulatory signals for T lymphocytes. Recently, defective expression of CD80 has been reported in systemic lupus erythematosus (SLE) although its mechanism is unclear. Here, expression of the B7 antigens induced by interferon-gamma, interleukin-4 or granulocyte-macrophage stimulating-factor (GM-CSF) along the differentiation process of APCs was investigated. In contrast to CD86, expression of CD80 on the CD14+ cells induced by GM-CSF was reduced in SLE. GM-CSF receptor (GM-CSFR) was down-regulated by GM-CSF or phorbol 12-myristate 13-acetate in both of the normal controls and SLE patients, while this change was more remarkable in the latter. In the presence of 1-(5-isoquinolinsulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C, the PMA-induced down-regulation of GM-CSFR was reversed in the normal controls but not in SLE. These data suggest that dysregulation of the GM-CSFR might be associated with the defective expression of CD80, leading to dysfunction of the APCs in SLE.
 ...
PMID:Dysregulation of the granulocyte-macrophage colony-stimulating factor receptor is one of the causes of defective expression of CD80 antigen in systemic lupus erythematosus. 1209 May 68

In the present study we have investigated the potential involvement of protein kinase C (PKC) in the maturation of human dendritic cells (DC) by bacterial lipopolysaccharide (LPS). LPS stimulation of DC derived from human monocytes resulted in PKC phosphorylation. Inhibition of PKC activation using bisindolylmaleimide (Bis), a pan-PKC inhibitor, was associated with a dose-dependent decrease of LPS-induced IL-12 production. In contrast, up-regulation of MHC class II, CD80 and CD86 was not altered. Consistent with the diminished IL-12 synthesis, DC stimulated with LPS in presence of Bis were deficient in the induction of IFN-gamma production by allogeneic CD4+ T cells. Furthermore, we found that PKC inhibition impaired LPS-induced I kappa B-alpha degradation and subsequent nuclear factor (NF)-kappa B activation in DC. LPS resulted in the phosphorylation of conventional alpha/beta and novel epsilon PKC isoforms in DC. Inhibition of LPS-induced PKC activity using pseudosubstrate peptides specific for PKC isoforms established that PKC epsilon but not PKC alpha/beta was involved in the production of IL-12 and TNF-alpha. Overall, these data provide evidence that PKC inhibition impairs LPS signaling in DC and identify PKC epsilon as a potential target for the inhibition of Toll-like receptor-4-mediated, IL-12-dependent Th1 type responses.
 ...
PMID:Critical role of protein kinase C epsilon for lipopolysaccharide-induced IL-12 synthesis in monocyte-derived dendritic cells. 1238 23

For T cell activation, two signals are required, i.e., a T cell receptor (TCR)/CD3-mediated main signal and a CD28-mediated costimulatory signal. CD28 binds to its ligand (CD80 or CD86) and transduces the most important costimulatory signal. The cytoplasmic domain of the CD28 molecule, composed of 41 amino acids, does not contain any intrinsic enzyme activity. The cytoplasmic domain of CD28 is remarkably conserved among species and is associated with a number of signaling molecules that affect the main signal. We report here that a tyrosine phosphorylated 100-kDa protein (ppl00) was coupled to the CD28 cytoplasmic domain in Jurkat and human peripheral T cells. The pp100 was distinguished from other CD28 associated molecules such as Vav, STAT5, PI 3-kinase, Valosin-containing protein (VCP), Nucleolin, Gab2 (Grb2-associated binding protein 2), and STAT6. The tyrosine phosphorylation of pp100 coprecipitated with CD28 was enhanced by CD3 stimulation by the specific antibody, tyrosine phosphatase inhibitor and PKC activator. Tyrosine phosphorylation of pp100 was attenuated by the prior addition of PKC inhibitor. These findings indicate that pp100 is a novel tyrosine phosphorylated protein coupled to CD28 under continuous control of tyrosine phosphatases and might play a role in T cell activation augmented by a TCR/CD3-mediated main signal.
 ...
PMID:Tyrosine phosphorylation of a novel 100-kDa protein coupled to CD28 in resting human T cells is enhanced by a signal through TCR/CD3 complex. 1263 55


1 2 3 4 Next >>