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)

Clonal T cell expansion requires simultaneous activation of the TCR and secondary signals, e.g. CD2, CD4, CD28. Interference of CD2/CD58 interaction with MoAbs abrogates the primary immune response and antibody production. Given this functional importance of CD2/CD58 interaction for the generation of specific immune responses, we demonstrate for the first time a defective CD2 pathway activation in patients with CVID (seven children and four adults). The costimulatory effect of monocytes upon CD2-triggered proliferation was significantly impaired in CVID patients: 4.080 ct/min versus 20.769 ct/min in controls (P < 0.05). Second, IL-1, which is a strong comitogenic factor for activation via CD2 in normal T cells, showed a defective amplifier function of the CD2 pathway in most patients (median 1.714 ct/min in patients versus 17.521 ct/min in controls; P < 0.05). In addition, by using a mitogenic combination of CD2 plus CD45 MoAb, median proliferation of T cells was severely depressed in patients: 10.577 ct/min versus 34.685 ct/min in controls (P = 0.005). In conclusion, the marked dysfunction seen in responsiveness to phytohaemagglutinin (PHA) (median 24.594 ct/min in patients versus 52.229 ct/min in controls; P < 0.001) and after CD2 triggering, together with the unaffected response to TCR-CD3, suggest that the T cell deficiency in CVID is in part due to deficiencies in the CD2 pathway. Since direct activation of protein kinase C(PKC) by phorbol ester restores defective T cell responses to normal, our results suggest that an early signal-transducing defect might exist at a step proximal to PKC activation in patients with CVID.
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PMID:Defective CD2 T cell pathway activation in common variable immunodeficiency (CVID). 791 May 35

The transmembrane tyrosine phosphatase CD45 plays an important role in TCR/CD3-mediated signaling. We demonstrate in this study that ligand binding to the CD45 molecule induces homotypic cell adhesion of activated, but not resting, T lymphocytes. mAbs to CD45 (4B2 and 10G10) and to CD45RO (UCHL1), but not to CD45RA (IOL2), caused sustained adhesion of alloreactive T cell lines. In contrast, none of the anti-CD45 mAbs induced aggregation of resting peripheral T cells. CD45-mediated adhesion of activated T cells involved both CD11a/18-dependent as well as CD11a/18-independent mechanisms. mAb 4B2 induced a strictly CD11a/18-dependent adhesion that was completely inhibited by both the protein kinase C (PKC) inhibitor sphingosine and the protein tyrosine kinase (PTK) inhibitors genestein and herbimycin A. In contrast, mAb 10G10, which recognized an epitope on CD45 distinct from the one recognized by mAb 4B2, induced CD11a/18-independent adhesion that was inhibited by sphingosine, but not by genestein or herbimycin A. Biochemical studies revealed direct evidence for activation of protein kinase C and protein tyrosine kinase after engagement of CD45 on activated T cells by mAb 4B2. These results indicate that in addition to its role in TCR/CD3-mediated activation, engagement of CD45 transduces signals that result in enhanced adhesiveness of activated T cells.
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PMID:Engagement of the common leukocyte antigen CD45 induces homotypic adhesion of activated human T cells. 791 42

MHC class II molecules play a central role in the control of the immune response, but their biologic function and mechanism of action on the surface of activated human T lymphocytes are not entirely understood. In our study, the functional role of HLA class II molecules in T-blast proliferation was investigated by analyzing in parallel the IL-2- and CD3-driven activation pathways. The results indicate that the cross-linking of class II and CD3 molecules significantly increased the CD3-mediated T-blast proliferation, while no effect was observed on the IL-2-driven cell activation. This phenomenon was not confined to either CD4+ or CD8+ subsets nor was specifically affected by CD45 triggering. Biochemical studies showed that signaling via MHC class II molecules in T blasts led to PKC membrane translocation and IP accumulation. The simultaneous triggering of CD3 and HLA class II molecules led to a synergistic effect on IP accumulation but did not increase the CD3-mediated PKC membrane translocation. Our data suggest that HLA class II molecules are involved in T-cell-T-cell interactions and can mediate accessory signals, affecting the T-lymphocyte activation state.
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PMID:HLA class II molecules transduce accessory signals affecting the CD3 but not the interleukin-2 activation pathway in T blasts. 813 20

In HPB-ALL T-cells the p59fyn tyrosine kinase is regulated by the CD45 phosphotyrosine phosphatase and plays a critical role in coupling the T cell receptor (TCR) to the generation of intracellular signals which include diacylglycerol (DAG) production and protein kinase C activation. The aim of this study was to determine the phospholipid pools from which the DAG is generated and to identify which phospholipase activities are regulated by the TCR. When CD45+ cells were pre-labeled with [3H]arachidonic acid, CD3-antigen cross-linking stimulated negligible increases in both [3H]DAG and [3H]phosphatidic acid (PA). However, CD3 monoclonal antibody (mAb) induced an increase of 300% in [3H]PA when the cells were permeabilized with streptolysin-O, and this correlated with increased levels of protein tyrosine phosphorylation. Stimulation of [3H]PA production upon CD3 cross-linking was 77% lower in permeabilized CD45- cells than in CD45+ cells, consistent with the reduced activity of p59fyn in CD45- cells. The stimulated production of PA was not mediated by activation of phospholipase D (PLD), although the presence of a G-protein-regulated PLD activity was established. The CD3-induced increase in total inositol phosphates (InsP) in permeabilized cells was similar to the stimulated production of [3H]PA production in both CD45+ and CD45- cells. Dose-response curves for InsP and PA production triggered by CD3 mAb were super-imposable and the production of InsP and PA over a range of Ca2+ concentrations was comparable. Differential labeling of phospholipids with 3H-labeled fatty acids revealed that CD3-induced PA production reflected incorporation of label into the phosphatidylinositol pool. Our data suggest that in HPB-ALL cells the production of DAG following CD3-antigen cross-linking can be fully accounted for by the selective coupling of the TCR to breakdown of phosphatidylinositol-(4,5)-bisphosphate as the result of phospholipase C gamma 1 activation. This event correlates with the activity of the CD45-regulated TCR-associated tyrosine kinase, p59fyn.
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PMID:Selective coupling of the T cell antigen receptor to phosphoinositide-derived diacylglycerol production in HPB-ALL T cells correlates with CD45-regulated p59fyn activity. 822 75

The CD45 protein is a transmembrane tyrosine phosphatase that is required for normal T and B cell receptor-mediated signaling. In order to study the function of this phosphatase in mast cells, we have isolated a CD45-deficient variant from the rat basophilic leukemia cell line (RBL-2H3), a tumor analog of mucosal mast cells. The secretory response as well as the inositol 1,4,5-triphosphate (InsP3) formation to Fc epsilon RI and ionophore stimuli were similar in the RBL-2H3 cell line and its derived CD45-deficient subpopulation. However, pretreatment with the phorbol ester TPA, which directly activates protein kinase C (PKC), caused a marked increase in mediator release and InsP3 production in the CD45-deficient variant compared to the parental RBL-2H3 cells. These findings suggest that CD45 might directly or indirectly modify the activity of PKC or the InsP3-dephosphorylating phosphatase.
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PMID:CD45-deficient RBL-2H3 cells. Cellular response to Fc epsilon R- and ionophore-induced stimulation. 830 Jan 59

CD53 is a member of a novel family of molecules with four presumably membrane-spanning domains. The structure and functional characteristics of these molecules indicate that they may play an important role in transmembrane communication. We therefore investigated whether CD53 is involved in activation of human leukocytes. Cross-linking of cell-bound F(ab')2 fragments of two different anti-CD53 mAb with F(ab')2 anti-mouse Ig led to cytoplasmic calcium fluxes in B cells, monocytes, and granulocytes and activation of the monocyte oxidative burst. These responses were specific for CD53, as cross-linking of CD11a, CD18, CD35, CD43, CD44, CD45, or CDw50 did not induce leukocyte activation. Low concentrations of staurosporine (10 to 20 nM) completely inhibited PMA-mediated activation, but had no effect on CD53-mediated calcium fluxes and inhibited only partially CD53-mediated oxidative burst. This suggests that CD53-mediated signaling is largely independent of protein kinase C. CD53-mediated calcium fluxes were inhibited by high concentrations of staurosporine (300 to 500 nM) but not by ADP-ribosylating toxins, suggesting dependence on tyrosine kinases rather than GTP-binding proteins. The results indicate that CD53, like several other leukocyte Ag with four membrane-spanning regions, has the ability to mediate cell activation, and support the view that these molecules are involved in transmembrane communication.
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PMID:CD53, a protein with four membrane-spanning domains, mediates signal transduction in human monocytes and B cells. 833 5

In rheumatoid arthritis and other inflammatory diseases we and others have found that gamma delta T cells express activation antigens, suggesting that they are involved in the pathogenesis of these disorders. In this study we have stimulated peripheral blood mononuclear cells from normal donors with recombinant interleukin-2 (rIL-2) to see whether such a stimulus alone could activate gamma delta T cells. Short-term exposure (24-96 h) to rIL-2 selectively stimulated the gamma delta but not the alpha beta T cells to express activation antigens (CD69, CD25 and HLA-DR). Long-term culture (2 weeks) in rIL-2-containing medium caused a selective increase in the proportion of the gamma delta T cells and a corresponding reduction of the fraction of alpha beta T cells. Limiting dilution analysis revealed that approximately 1/60 of the gamma delta T cells responded to IL-2 in contrast to only 1/250 of the alpha beta T cells. Comparison of the expression of the IL-2 receptor (IL-2R) alpha and beta chains showed that there was a similar expression of the alpha chain on gamma delta and alpha beta T cells whereas the relative density of the beta chain was more than twice as high on gamma delta T cells. Both the IL-2-induced proliferation of gamma delta T cells and the expression of activation antigens on these cells could be inhibited by an anti-IL-2R beta monoclonal antibody (mAb) but not by an anti-IL-2R alpha mAb. Expression of CD69 on gamma delta T cells was dependent neither on the presence of B cells, monocytes, nor alpha beta T cells. Finally, we found that the IL-2-induced expression of CD69 was inhibited by activation of cAMP-dependent protein kinase and by inhibition of the Src-family of the tyrosine protein kinase, but not by inhibition of protein kinase C or by activation of the CD45 associated tyrosine phosphatase. The ability of gamma delta T cells to be activated by IL-2 is a feature which they have in common with natural killer cells. Moreover, it may be possible that the expression of activation antigens on gamma delta T cells in inflammatory diseases is an epiphenomenon secondary to IL-2 produced by activated alpha beta T cells.
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PMID:Selective activation of resting human gamma delta T lymphocytes by interleukin-2. 837 Mar 91

In this study, we examined whether CD45 isoform can be switched in murine mature B cells and what signals are responsible for the process. Stimulation of murine splenic B cells with lipopolysaccharide did not reduce the expression of CD45RA-, B-, and C-exon-dependent epitopes or a CD45 common epitope, but rather enhanced the expression. Stimulation with goat antimouse IgM antibody did not significantly reduce CD45 expression but caused a partial reduction in the expression of CD45RA-, B-, and C-exon-dependent epitopes. Phorbol myristate acetate (PMA) alone did not significantly alter the expression of CD45 but the combination of PMA and ionomycin induced a strong reduction in the expression of CD45RA-, B-, and C-exon-dependent epitopes without affecting the level of CD45 common epitope expression. Reverse transcription and polymerase chain reaction analysis demonstrated that CD45 isoform switch induced by anti-IgM or PMA plus ionomycin is indeed mediated by alternative splicing of A-, B-, and C-exon-derived mRNA. These results suggest that CD45 isoform of murine mature B cells can be switched by antigen receptor-mediated signals, and the process seems to be regulated at least in part by protein kinase C activation and mobilization of calcium ions.
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PMID:Induction of CD45 isoform switch in murine B cells by antigen receptor stimulation and by phorbol myristate acetate and ionomycin. 840 33

The c-Raf-1 serine/threonine kinase is an important component of signal transduction pathways mediating the effects of a variety of growth factors. In activated T cells, IL-2 has been shown to induce activation of c-Raf-1, but c-Raf-1 has not previously been shown to be activated through the T-cell receptor (TCR) in resting G0 T cells. Using a sensitive immune complex kinase reaction, we show that cross-linking of the stimulatory and costimulatory receptors CD3, CD4, or CD28 induces c-Raf-1 activation in highly purified resting peripheral blood human T cells. In contrast, cross-linking the nonstimulatory receptor CD45 did not induce c-Raf-1. Surprisingly, although earlier studies had shown delayed kinetics in response to Thy-1 stimulation in murine cells, c-Raf-1 activation in response to CD3 cross-linking was one of the earliest measurable events. In spite of its early kinetics, c-Raf-1 activation was found to be downstream of several other early signal transduction events, including activation of a tyrosine kinase and a tyrosine phosphatase. Several lines of evidence suggest that activation of c-Raf-1 in response to TCR stimulation may be PKC-dependent: first, phorbol esters are extremely potent activators of c-Raf-1 in human T cells; second, the kinetics of accumulation of products of phosphatidylinositol hydrolysis coincides with the kinetics of c-Raf-1 activation; and third, physiologic activation of the PLC/PKC pathway through a transfected, G-protein-coupled receptor HM1 induced similar levels of c-Raf-1 activation with a similar time course. We conclude that c-Raf-1 activation is tightly coupled to TCR stimulation and may participate in signal transduction pathways in resting, G0 T cells. The observation that the HM1 receptor can also activate c-Raf-1 suggests that T cells have the capability to utilize both tyrosine kinase-dependent and tyrosine kinase-independent mechanisms of c-Raf-1 activation.
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PMID:Rapid activation of C-Raf-1 after stimulation of the T-cell receptor or the muscarinic receptor type 1 in resting T cells. 840 89

T lymphocytes may be separated into subsets according to their expression of CD45 isoforms. The CD45R0+ T cell subset has been reported to proliferate in response to recall antigen and to mitogenic mAb to a much greater extent than the CD45RA+ subset. This difference could be due to more efficient coupling of the T cell antigen receptor complex to mitogenic signaling pathways. To investigate this possibility, CD3 antigen-induced calcium signals, diacylglycerol (DAG) production and protein kinase C (PKC) activation levels were compared in CD45RA+ and CD45R0+ human T lymphocyte subsets derived from peripheral blood. The mean CD3-induced rise in intracellular calcium was 80% greater in CD45R0+ than in CD45RA+ cells. Basal DAG levels in CD45R0+ cells were found to be, on average, 60% higher than in CD45RA+ cells (p = 0.002), but the CD3-induced production of DAG over background was not different in the two subsets (p = 0.4). Basal PKC activity, and CD3-induced PKC activation levels over background, were found to be 50% and 140% higher, respectively, in CD45R0+ cells than in CD45RA+ cells (p = 0.015 and 0.023). The CD45R0+ subset contained a higher proportion of cells expressing activation markers, such as CD25, CD71 and major histocompatibility complex class II, when compared to the CD45RA+ subset. Our results suggest that the elevated basal DAG levels observed in the CD45R0+ subset may reflect the recent activation of these cells. Both the higher basal DAG and CD3-induced elevation in intracellular calcium observed in the CD45R0+ cells may contribute to the greater PKC activation signals triggered by CD3 mAb in this subset. These findings elucidate the greater response of CD45R0+ T cells to mitogenic stimuli compared to CD45RA+ cells.
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PMID:CD3 antigen-mediated calcium signals and protein kinase C activation are higher in CD45R0+ than in CD45RA+ human T lymphocyte subsets. 841 89


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