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)

Tac antigen, the receptor for human interleukin 2 (IL-2), contains in its intracytoplasmic region a serine residue (Ser-247) that is seemingly the predominant site of protein kinase C-mediated phosphorylation. A number of studies on growth factor receptors have suggested the importance of phosphorylation in receptor structure, function, and regulation. In this study, we generated site-directed mutations in the Tac antigen cDNA to generate mutant receptors in which Ser-247 or Thr-250, a probable site of minor phosphorylation, was replaced with another amino acid that is not accessible to phosphorylation. Study of the expression of these mutant genes in a T-lymphoid cell line has provided no evidence as to the essential role of the above-mentioned residues in determining the degree of receptor affinity, its ability for signal transduction, and phorbol ester-mediated regulation of the receptor. Our results strongly suggest the existence of an IL-2 receptor "complex" in which the Tac antigen is associated with another molecule(s) that is involved in receptor structure, function, and regulation.
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PMID:Intracytoplasmic phosphorylation sites of Tac antigen (p55) are not essential for the conformation, function, and regulation of the human interleukin 2 receptor. 309 87

T lymphocytes respond to mitogenic stimulation by expressing the receptor for interleukin 2 (Il-2) and secreting Il-2; once the receptor is expressed, Il-2 induces these cells to proliferation. In the present report using mouse T lymphocytes, thymocytes, and the lymphoma cell line EL4, we studied receptor expression and Il-2 secretion as early parameters for T-lymphocyte activation in response to ionomycin, concanavalin A (Con A), 12-O-tetradecanoyl-phorbol 13-acetate (TPA), and interleukin 1 (Il-1). Il-1 is required for mitogenic response of lymphocyte preparations that are rigorously depleted of macrophages. On its own, Il-1 had very little effect on Il-2 secretion and Il-2 receptor expression by T lymphocytes. TPA strongly synergized with ionomycin both for Il-2 secretion and for Il-2 receptor expression whereas Il-1 did not. Il-1 required the simultaneous presence of ionomycin and TPA to have any demonstrable effect on T lymphocytes from spleen and on thymocytes. However, on EL4 cells which were also partially responsive to TPA alone, Il-1 showed strong synergy with TPA to induce Il-2 secretion and Il-2 receptor expression. The effect of Il-1 on EL4 cells was dose dependent where increasingly higher concentrations of Il-1 in the presence of a fixed concentration of TPA caused higher percentage of EL4 cells to become Il-2 receptor positive. The present results suggest that Il-1 does not cause its effect on T lymphocytes via the same mechanism of protein kinase C activation that has been proposed for TPA.
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PMID:Interleukin 1 and protein kinase C activator are dissimilar in their effects on Il-2 receptor expression and Il-2 secretion by T lymphocytes. 310 60

1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a protein kinase inhibitor, suppressed interleukin 2 (IL-2) production and IL-2 receptor (IL-2R) expression of the human leukemic T-cell line, Jurkat, induced by 12-O-tetradecanoyl-phorbol-13-acetate and phytohemagglutinin-P. This effect was significant at 5 microM H-7 without loss of cell viability. Such activity was not observed with N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA 1004), a potent inhibitor of cGMP- and cAMP-dependent kinases, and a weak inhibitor of Ca2+-phospholipid-dependent protein kinase (protein kinase C). These findings suggest that protein kinase C is more closely associated with IL-2 receptor expression and IL-2 production of T cells than cGMP- or cAMP-dependent kinases. In addition, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), a calmodulin inhibitor, suppressed both IL-2 production and IL-2R expression. Cycrosporin A (Cy A), a potent immunosuppressive drug, markedly inhibited IL-2 production of Jurkat cells whereas it did not affect the IL-2R expression. Thus, the mechanism of action of Cy A appears to differ from that of the protein kinase inhibitor, H-7, and the calmodulin inhibitor, W-7.
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PMID:Inhibitors of IL-2 production and IL-2 receptor expression in human leukemic T-cell line, Jurkat. 310 62

Class I major histocompatibility antigens in humans (HLA antigens) were found to participate in the regulation of T-cell activation and proliferation induced by phytohemagglutinin. W6/32, a monomorphic antibody directed against class I HLA-A,B,C antigens, significantly inhibited the phytohemagglutinin-induced cell proliferation of peripheral blood lymphocytes. Almost complete suppression of cell activation was achieved on a subfraction of peripheral blood lymphocytes enriched in Mo1+ monocyte/macrophage cells. This inhibition of cell proliferation takes place at an early stage of activation and was found to be adherent cell dependent. Removal of monocyte/macrophage type cells from peripheral blood lymphocytes completely abrogated the inhibitory influence of anti-HLA-class I antibody, and, upon adding them back, suppression reappeared. Indirect immunofluorescence demonstrated that the expression of receptors for interleukin 2 and transferrin was impaired in the presence of antibody. Although the amount of interleukin 2 synthesized by these cells was also reduced, the addition of exogenous purified interleukin 2 did not restore cell proliferation. Mitogenesis induced by the Ca2+ ionophore A23187 was similarly suppressed, but mitogenesis induced by the phorbol diester phorbol myristate acetate, which activates cells by directly stimulating protein kinase C, was not suppressed. These results are consistent with a hypothesis that HLA class I antigens regulate an early event(s) of the Ca2+-dependent pathway of activation of T lymphocytes and that this event(s) apparently occurs before protein kinase C stimulation.
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PMID:The role of class I histocompatibility antigens in the regulation of T-cell activation. 310 25

High density (resting) murine Lyt-2+ T cells exposed in vitro to the ligand concanavalin A (Con A) remain interleukin 2 (IL 2) unresponsive, i.e. do not express functional IL 2 receptors, unless reconstituted with accessory cells. This finding provides a bio-assay to define functional and biochemical characteristics of an IL 2 receptor-inducing factor (RIF). RIF bioactivity as secreted from the macrophage cell line P388-D1 is associated with a trypsin-sensitive protein of 44 kDa which does not need to be glycosylated and which binds to and can be eluted from hydroxylapatite and phenyl-Sepharose. While both RIF and IL 1 are produced by accessory cells the lymphokines separate from each other according to functional and biochemical criteria. Either accessory cells, RIF or the protein kinase C activator phorbol myristate acetate can substitute for each other and are equally active for the induction of IL 2 responsiveness in high-density Lyt-2+ T cells exposed to Con A. To explain these results we conclude that in the mitogen system used, induction of IL 2 responsiveness (activation) represents a two-step event in which first cross-linking of cell surface structures by the ligand Con A excites the responder T cells, which subsequently respond to the accessory cell product RIF.
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PMID:Functional and biochemical characteristics of a murine interleukin 2 receptor-inducing factor. 310 61

Biochemical signals required for the growth of T cell clones were studied. Antigen-specific helper T cell clones, 6-1 and KO.6, could enter the state similar to the resting state where the cells expressed only small numbers of interleukin 2 (IL2) receptors and could not respond to IL2 without antigenic stimulation. A combination of a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), and a calcium ionophore, A23187, induced the expression of IL2 receptors on resting 6-1 cells and induced DNA synthesis in the presence of IL2. TPA alone did not induce IL2 receptors. A23187 induced the expression of the receptors to some extent but did not induce DNA synthesis even in the presence of IL2. IL2 receptors induced by A23187 alone were mostly low affinity receptors, whereas the combination of TPA and A23187 induced high affinity receptors in addition to low affinity receptors. Resting KO.6 cells produced IL2 in response to a combination of TPA and A23187, whereas either one of the agents did not induce the production of IL2. Dicaprylin, a permeable diacylglycerol and a potent activator of protein kinase C (the Ca2+/phospholipid-dependent enzyme) could replace TPA in both cases when dicaprylin was repeatedly added to the culture. These results suggest that strong and continuous activation of protein kinase C together with calcium mobilization is required for IL2 production and IL2 receptor expression. On the contrary, signals for DNA synthesis generated by binding of IL2 to IL2 receptors are different from those for IL2 production and IL2 receptor expression, as the combination of TPA and A23187 could not induce DNA synthesis without IL2.
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PMID:Signals for activation and proliferation of murine T lymphocyte clones. 310 23

We investigated whether the protein kinase C-binding agents 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and 1-oleoyl-2-acetyl-rac-glycerol (OAG) induced reactivity to interleukin 2 (IL-2) in mouse lymphocytes. 10(-8) M TPA was a strong inducer of reactivity to IL-2 measured by [3H]thymidine incorporation. In contrast OAG alone (6-25 micrograms/ml) did not induce a significant IL-2 mediated proliferative response. Cells stimulated with the ionophore A 23187 + OAG neither proliferated nor produced IL-2. In contrast, cells stimulated with A 23187 + OAG + IL-2 showed a significant proliferative response, indicating the expression of functional high affinity IL-2 receptors. The expression of reactivity to IL-2 induced by A 23187 + OAG was inhibited by 0.04 mM Mn2+; in contrast the TPA-mediated induction of IL-2 responsiveness was not affected by Mn2+. The data suggest differences in the mechanism of induction of IL-2 responsiveness by the two protein kinase C-binding agents, TPA and OAG.
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PMID:Induction of responsiveness to interleukin 2 in mouse lymphocytes by synergistic action of ionophore A 23187 and diacylglycerol. 311 32

In the present work we have used monoclonal antibodies (mAb) as probes to attempt a dissection of the mechanisms underlying the immunodeficiency subsequent to bone marrow transplantation (BMT). To this end we have studied 19 allogeneic BMT recipients, analyzing the proliferative response of peripheral blood mononuclear cells (PBMC) after activation with either phytohemagglutinin (PHA), anti-CD3 or anti-CD2 mAb. All patients presented normal proportions of CD2+ and CD3+ lymphocytes, as assessed by flow cytometry. Our results indicated that in most cases both CD2 and CD3-mediated activation pathways were inefficient to trigger normal T cell proliferation. The addition of exogenous interleukin 2 (IL2) did not restore in most cases the proliferative response, pointing out that additional defects contribute to the hyporesponsiveness. This was more evident in the group of patients studied during the first 6 months. To further dissect the T cell defect we analyzed the effect of a phorbol ester (phorbol myristate acetate, PMA), which activates protein kinase C, on the anti-CD3-induced response. Our data showed that PMA synergized with anti-CD3 similarly to exogenous IL2, and restored the proliferative response only in certain cases. The expression of IL2 receptors (CD25) as assessed by cytofluorimetry, after either PHA or anti-CD3 and PMA stimulation, was shown to be depressed, and the addition of IL2 did not restore it. Finally, we observed that the early increase of intracytoplasmic Ca2+ after anti-CD3 stimulation was comparable to that detected in normal PBMC. Altogether these results indicate that a diminished CD25 expression is associated with the T cell defect, and cannot apparently be attributed to an inability of the CD3 molecule to transduce early activation signals thus suggesting that either protein kinase C itself or an as yet undefined metabolic step preceding IL2 receptor expression is abnormal in variable proportions of T cells after BMT, and constitutes another manifestation of this complex immunodeficiency.
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PMID:Defective interleukin 2 receptor expression is associated with the T cell disfunction subsequent to bone marrow transplantation. 311 80

Human peripheral blood T lymphocytes were treated with phorbol myristate acetate (PMA), an activator of protein kinase C (PKC) activity, and with the calcium ionophore A23187. The resulting accumulation of specific mRNA for interleukin 2 (IL-2) and interleukin 2 receptor (IL-2R), as well as IL-2 secretion and membrane IL-2R expression were examined. At low concentrations (0.1 microM), A23187 synergized maximally with PMA to induce proliferation, to increase IL-2R mRNA levels and the expression of membrane IL-2R, and to produce a low but sufficient accumulation of IL-2 mRNA and IL-2 secretion. A high concentration of A23187 (1.0 microM) did not show any synergism for the accumulation of IL-2R mRNA, membrane IL-2R expression and inhibited the proliferation of PMA co-stimulated T cells. It did, however, induce maximum accumulation of IL-2 mRNA and IL-2 secretion.
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PMID:Regulation of interleukin 2 and interleukin 2 receptor gene expression in human T cells: I. Effect of Ca2+-ionophore on phorbol myristate acetate co-stimulated cells. 311 57

The murine Ly-6A.2 and Ly-6E.1 antigens, which can transduce triggering signals in T cells, have been shown to become highly expressed after mitogenic stimulation. It has recently been found that enhanced expression of Ly-6A/E antigens is also induced by interferon-gamma (IFN-gamma) in resting T cells. Here, the possibility is investigated that Ly-6A/E induction on activated T cells may be due to the IFN-gamma known to be secreted by these cells. A potent neutralizing anti-IFN-gamma monoclonal antibody (mAb) (H-22.10) was used. This mAb was found to abrogate the augmentation of Ly-6A/E antigens produced in resting T cells by supernatants from T cells stimulated with concanavalin A. When added directly into cultures of T cells stimulated with concanavalin A or by the combination of ionomycin with the protein kinase C activator phorbol myristate acetate (PMA), the H-22.10 mAb inhibited Ly-6A/E enhancement without affecting the blastogenesis or the emergence of interleukin 2 receptors and transferrin receptors. Such a selective effect of the anti-IFN-gamma mAb indicated that IFN-gamma is involved in the up-regulation of Ly-6A/E antigens during T cell activation. In determining whether other activation signals, in addition to IFN-gamma receptor occupancy, may contribute to Ly-6A/E enhancement, it was found that suboptimal stimulation of BALB/c T cells provided by a 3-hr pulse with ionomycin plus PMA or by culture with PMA alone potentiated by about twofold the increase of Ly-6E.1 induced by exogenous IFN-gamma. Therefore, Ly-6A/E augmentation in activated T cells reflects primarily an action of endogenous IFN-gamma that is amplified (in BALB/c mice) by a protein kinase C-dependent step.
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PMID:The augmentation of surface Ly-6A/E molecules in activated T cells is mediated by endogenous interferon-gamma. 312 27


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