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)

The regulation of the activation of T lymphocyte proliferation is not well understood. It is known that the tumor promoter, PMA, which activates protein kinase C (PKC), can induce the proliferation of several murine CTL clones; in combination with calcium ionophores, which raise the level of intracellular Ca2+, PMA can also stimulate the proliferation of several HTL clones. Activation of the TCR is believed to result in the liberation of diacylglycerol, which is an activator of PKC, and inositol 1,4,5-trisphosphate, which stimulates an increase in intracellular levels of calcium. We now report that pretreatment with cholera toxin (CT) inhibits the proliferation of murine T cell clones stimulated through the TCR/CD3 complex. In addition, CT-pretreatment blocks the proliferation of CTL clones activated with PMA or of HTL clones activated with PMA + calcium ionophore. In contrast, CT-pre-treatment inhibits much less effectively (100- to 1000-fold) the proliferation of these T cell clones stimulated with IL-2. Furthermore, activators of PKC, but not IL-2, potentiate the CT-induced cAMP elevation in T cell clones. The ability of CT to inhibit much more effectively the proliferation triggered by putative activators of PKC than that induced by IL-2 may be mediated by cAMP-dependent mechanisms.
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PMID:Cholera toxin discriminates between murine T lymphocyte proliferation stimulated by activators of protein kinase C and proliferation stimulated by IL-2. Possible role for intracellular cAMP. 284 87

TCR modulation induced by anti-TCR or anti-CD3 mAbs leads to a transient state of refractoriness of the T cell to all signals given via cell surface structures. To investigate the underlying mechanisms, we have used human CTL permeabilized with the alpha toxin of S. aureus. This method of permeabilization allows manipulation of the interior milieu of the cell, but maintains its functional and structural integrity. Introduction of the G protein activator GTP gamma S into permeabilized CTL leads to triggering of granule exocytosis. The G protein inactivator GDP beta S inhibited exocytosis induced by TCR triggering but not that induced by activation of protein kinase C. This indicates that the G protein that triggers exocytosis is localized after CD3 triggering but before formation of the polyphosphoinositol breakdown product diacylglycerol. In TCR-modulated CTL, GTP gamma S is no longer able to activate exocytosis. Such CTL, however, still respond to PKC activators. This demonstrates that a TCR-associated G protein has been functionally inactivated by TCR modulation.
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PMID:Inactivation of a T cell receptor-associated GTP-binding protein by antibody-induced modulation of the T cell receptor/CD3 complex. 297 May 22

We have shown previously that stimulation of cloned murine T lymphocytes via the TCR inhibits their responsiveness to rIL-2. Signaling via the TCR is believed to result in a variety of biochemical events that include a rise in intracellular free calcium and activation (translocation) of protein kinase C. These two signals also can be generated by calcium ionophores, such as ionomycin, and by activators of protein kinase C, such as PMA. We report here that treatment of cloned murine T lymphocytes with PMA, ionomycin, or the combination led to a dose-dependent inhibition of IL-2-dependent proliferation but did not inhibit lymphokine secretion. Concentrations of PMA and ionomycin that maximally inhibited proliferation stimulated maximal lymphokine secretion and increased mitochondrial activity as assessed by measurement of cleavage of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium-bromide. Furthermore, PMA, ionomycin, the combination, or immobilized anti-CD3 mAb added after 12 to 16 h of culture with IL-2 could inhibit proliferation. These results demonstrate that PMA and ionomycin mimic stimulation of the TCR by high concentrations of immobilized anti-TCR mAb in that proliferation is inhibited and lymphokine secretion is induced. In addition, PMA or ionomycin could independently inhibit proliferation of some cells. These findings suggest that alternative mechanisms exist to regulate proliferation. Either increased levels of intracellular calcium or the physiologic events corresponding to those induced by PMA can inhibit IL-2-dependent replication of T lymphocytes.
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PMID:Agents that mimic antigen receptor signaling inhibit proliferation of cloned murine T lymphocytes induced by IL-2. 314

To study the subcellular events occurring after T cell activation we used cloned human CTL permeabilized with alpha-toxin of Staphylococcus aureus. This method of permeabilization leads to stable transmembrane channels that permit the introduction of small molecules into the cell but preserves the cellular structures and macromolecular contents of the CTL. We used the exocytosis of CTL-specific serine esterases as a marker of T cell activation. The TCR-activated exocytosis is functioning in such permeabilized CTL. Introduction of the membrane impermeable guanosine nucleotide-binding protein (G-protein) activating GTP-analog GTP gamma S into CTL triggers exocytosis if Ca2+ is present. For optimal exocytosis ATP is required. The G-protein inactivating GDP-analog GDP beta S inhibited exocytosis triggered via the TCR-CD3 complex but not that triggered by activating the protein kinase C. If the protein kinase C was depleted in CTL by overnight incubation with phorbolester, the response to GTP-gamma S was reduced by more than 50%. These experiments demonstrate the presence of a G-protein involved in TCR-mediated CTL triggering. In the sequence of signaling steps this G-protein is localized after TCR-triggering but before the formation of the protein kinase C-activating phosphoinositol breakdown product diacylglycerol in the sequence of signaling steps.
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PMID:A T cell receptor-associated GTP-binding protein triggers T cell receptor-mediated granule exocytosis in cytotoxic T lymphocytes. 314 5

Activation of the enzyme protein kinase C (PKC) plays an important role in T cell activation. We investigated the phosphorylation of CD2, CD3, CD4, CD5, CD7, CD8, CD28 (Tp44), CD43 (sialophorin, gp115), and LFA-1 after incubation of human PBMC with the (PKC) activator PMA. These proteins were chosen for their role in transmembrane signal transduction (CD2, CD3, CD5, CD28, CD43), cell-cell interaction and adhesion (CD2, CD4, CD8, and LFA-1), or involvement in immunodeficiency states (CD43, CD7). CD5, CD7, CD43, and the alpha-chain of LFA-1 were found to be constitutively phosphorylated. PMA induced rapid hyperphosphorylation of CD5, CD7, and CD43, but not of the LFA-1 alpha-chain, and induced the phosphorylation of CD3, CD4, CD8 and of the LFA-1 beta-chain. PMA did not cause the phosphorylation of CD2 and CD28. PMA-induced phosphorylation was partially inhibited by the PKC inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride. Finally, the T cell activator Con A, which binds to the CD3/TCR complex was shown to induce a profile of protein phosphorylation similar to that observed with PMA. We conclude that PKC-mediated phosphorylation of T cell Ag may represent an important regulatory mechanism that governs the process of T cell activation.
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PMID:Phosphorylation of T cell membrane proteins by activators of protein kinase C. 325 10

The regulation of expression of the TCR-alpha and -beta genes was studied in the human T cell tumor line Jurkat. Treatment of the cells with PMA was shown to decrease the surface expression of the TCR-alpha/beta/CD3 complex. Subsequent to PMA-induced modulation of the TCR/CD3 complex, increases in the mRNA levels of both the TCR-alpha and -beta genes were observed reaching a maximum 12 h after stimulation. Other T cell activators were also examined for their ability to increase TCR-alpha and -beta mRNA expression. Only agents that activate protein kinase C were shown to induce expression of the TCR-alpha and -beta genes. The observed increases in TCR-alpha and -beta gene mRNA levels were not the result of a uniquely derived Jurkat subline. Similar inductions of TCR-alpha and -beta mRNA levels were observed in an independently maintained Jurkat cell line. In both cell lines, elevations of TCR gene expression was accompanied by a decline in the expression of the c-myc proto-oncogene. PMA induction of TCR-alpha and -beta mRNA was shown to occur in the presence of the protein synthesis inhibitor cycloheximide. The 1.6-kb TCR-alpha and the 1.0-kb D beta J beta C beta TCR-beta gene transcripts were fully induced in the presence of cycloheximide, whereas the 1.3-kb V beta D beta J beta C beta transcript was only partly induced in the presence of cycloheximide. Run-on transcription assays demonstrated that the increase in TCR-alpha and -beta mRNA levels could be entirely accounted for by increases in the transcription rate of both genes after PMA induction. Thus, in summary, protein kinase C stimulation leads to TCR-alpha/beta modulation in Jurkat cells and an increase in steady state TCR-alpha and -beta mRNA levels as a result of transcriptional activation of both genes.
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PMID:Transcription of T cell antigen receptor genes is induced by protein kinase C activation. 326 60

TCR stimulation by Ag or anti-receptor antibodies in murine T cells results in the activation of two independent protein kinases, protein kinase C (PKC) and a protein tyrosine kinase. Similarly, stimulation of murine Thy-1 or Ly-6 with mAb also results in activation of both of these kinase pathways. Tyrosine phosphorylation in all cases occurs on the TCR zeta-chain. It is known that Ag and anti-receptor antibodies activate PKC in human T cells. In this study we demonstrate that mitogen or anti-CD3 antibodies activate tyrosine phosphorylation of the human TCR-zeta-chain. PMA, which activates PKC, does not result in zeta-chain tyrosine phosphorylation. Stimulation of human T cells by antibodies that bind the CD2 molecule is an alternate mode of inducing T cell proliferation. These antibodies surprisingly do not induce tyrosine phosphorylation of the zeta-chain. Thus, different methods of cellular activation can result in distinguishable patterns of receptor-mediated biochemical signaling events.
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PMID:Tyrosine phosphorylation of the human T cell antigen receptor zeta-chain: activation via CD3 but not CD2. 326 30

The CD28 molecule expressed on the surface of T cells plays a pivotal role in transducing costimulatory signals necessary for cell activation. CD28 coligation enhances tyrosine phosphorylation and phosphoinositol 3-kinase association in responsive cells. CD28 cross-linking has also been reported to activate inositol phospholipid turnover and to cause release of intracellular calcium. Here we examine the effects of CD28 cross-linking on early activation of protein kinase C (PKC). We have reported recently that either PMA or CD28 cross-linking synergizes with signals delivered by superantigen and cytokines to induce the proliferation of APC-depleted T cells. Unlike PMA, CD28 cross-linking alone failed to induce an increase in membrane-associated PKC activity. However, PKC activation was seen in resting T cells when CD28 was cross-linked in the presence of superantigen plus APC-derived supernatant, which by themselves had no effect on PKC activity. Inhibition of PKC activity using calphostin C blocked the response of pure T cells to superantigen in the presence of either autologous APC, PMA, or CD28 cross-linking. This effect was specific; it was only seen when calphostin C was added within the first hour of stimulation. Assays of [Ca2+]i levels showed that CD28 cross-linking augmented and prolonged the rise in [Ca2+]i induced in T cells by superantigen and APC-derived cytokines. In the presence of superantigen, the proliferative response of T cells costimulated by CD28 cross-linking was cyclosporin A-sensitive, whereas in the presence of PMA, CD28 cross-linking conferred resistance to cyclosporin A. Both the phosphorylation of phospholipase C gamma 1 at tyrosine and the rise in [Ca2+]i induced by CD28 cross-linking in preactivated T cells were blocked by herbimycin A. Herbimycin A treatment also blocked the ability of CD28 cross-linking to induce a rise in [Ca2+]i in resting T cells. We conclude that CD28 costimulatory signals augment superantigen-induced TCR signals by converging onto common TCR effector pathways involving the activation of phospholipase C gamma 1 and PKC and by generating a cyclosporin A-sensitive pathway.
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PMID:CD28 cross-linking augments TCR-mediated signals and costimulates superantigen responses. 753 90

This study examined the role of protein tyrosine kinase (PTK) and protein kinase C (PKC) in the signal transduction pathways for lymphocyte activation through IL-2R to generate LAK cells and through TCR-CD3 to generate CD3-AK cells. Two PTK inhibitors [herbimycin A and genistein (PTK-I)] and two PKC inhibitors [calphositin C and staurosporine (PKC-I)] were used in the experiments. It was found that the primary activation pathway through IL-2R was PTK-dependent; that is, generation of both the IL-2-induced proliferative and the cytotoxic responses was completely abrogated by PTK-I and not by PKC-I. Quite different results were obtained with the alpha CD3-induced CD3-AK cell response. First, the alpha CD3-induced proliferation was only partially inhibited by PTK-I or PKC-I alone. Second, generation of CD3-AK cytotoxic response was primarily PKC-dependent; that is, only PKC-I induced significant inhibition. Genistein was found to reduce protein tyrosine phosphorylation in both LAK cells and CD3-AK cells, indicating that CD3-AK cells were also susceptible to PTK-I treatment. Further studies showed that PTK-I and not PKC-I suppressed perforin mRNA expression and N-2-benzyoxycarbonyl-L-lysine thiobeneylester esterase production in LAK cells, and the opposite was true for CD3-AK cells. These results indicate that different pathways were employed in lymphocyte activation through IL-2R and TCR-CD3. The former pathway is primarily PTK-dependent. Activation through TCR-CD3 is a more complex event.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential requirement of protein tyrosine kinase and protein kinase C in the generation of IL-2-induced LAK cell and alpha CD3-induced CD3-AK cell responses. 753 36

In T cell hybridomas, TCR/CD3 complex-mediated stimulation induces apoptosis but inhibits that induced by glucocorticoids. A combination of ionomycin (IM), a calcium ionophore, and PMA, a protein kinase C activator, mimics the effects of the TCR/CD3-mediated stimulation. Glucocorticoid-induced apoptosis is, however, markedly inhibited by IM alone, and less markedly by PMA alone. The immunosuppressant FK506 canceled the inhibition by IM but not that by PMA. As calcineurin (CN) is one of the target molecules of FK506, we examined whether CN activation might have an anti-apoptotic effect. BOG8, a T cell hybridoma, was stably transfected with a mutant CN catalytic subunit with Ca2+/calmodulin-independent, constitutive but FK506-sensitive phosphatase activity. The transfectant clones were fairly resistant to glucocorticoid-induced death. Their resistance, however, was hardly affected by FK506 when added simultaneously with glucocorticoid, but was lost after a prolonged preincubation with FK506. In the parent BOG8 cells, FK506 failed to cancel the inhibitory effect of IM on glucocorticoid-induced death when the addition of FK506 was delayed for 1 h or more. These results suggest that CN activation is required for the resistance only as an early event. The transfectant clones produced IL-2 but failed to undergo apoptosis upon stimulation with PMA alone, whereas apoptosis was induced by a combination of IM and PMA. These results suggest that activation-induced cell death may require a higher level of CN activity than IL-2 production or may require another Ca(2+)-dependent pathway.
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PMID:Calcineurin activation protects T cells from glucocorticoid-induced apoptosis. 753 18


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