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)

We have studied an 8-yr-old male patient with adenosine deaminase-positive severe combined immunodeficiency disease with a normal number of peripheral CD3+, T cell receptor-alpha beta+ T cells. The majority of these T cells expressed the CD8 molecule and were oligoclonal in nature as proven by Southern blot analysis of the T cell receptor genes. T cells failed to proliferate in vitro either upon stimulation with T cell mitogens or when stimulated with a combination of the phorbol ester phorbol myristate acetate and the Ca-ionophore ionomycin. High doses of recombinant IL-2, when added to in vitro cultures, were able to restore proliferation induced by phorbol myristate acetate and ionomycin but the response to concanavalin A remained severely defective. However, activation of the patient's T cells with phytohemagglutinin or concanavalin A induced an increase of free cytoplasmic Ca++, which was 2- to 5-fold higher than in normal CD8+ T cells. Furthermore, phorbol myristate acetate or phytohemagglutinin induced the translocation of protein kinase C from cytosol to plasma membrane. Analysis of membrane phospholipid composition of the patient's T cells disclosed that the ratio of phosphatidylcholine to phosphatidylserine was 5-fold higher than in normal T cells. The abnormal Ca++ response after activation with T cell mitogens as well as the high phosphatidylcholine/phosphatidylserine ratio may be causally linked to the defective in vitro T cell proliferation. Because the capacity of T lymphocytes to produce or respond to IL-2 may vary, the oligoclonality of the T cells of the patient should be considered as well in the explanation of defective cell proliferation.
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PMID:Abnormal signal transduction in a patient with severe combined immunodeficiency disease. 190 23

The general way to induce the synthesis of lymphokines by T cells is the stimulation through the T cell receptor (TcR) complex which results in an increase of intracellular [Ca2+] and in the activation of a tyrosine kinase as well as of protein kinase C. Lymphokine production induced via the TcR is inhibited by the immunosuppressive drug cyclosporin A (CsA). However, an alternative pathway of lymphokine production exists. Several T lymphocyte clones can synthesize interferon-gamma (IFN-gamma), granulocyte-monocyte colony-stimulating factor, and small amounts of interleukin (IL3) when stimulated with syngeneic or allogeneic accessory cells (AC) plus IL2. In contrast to the TcR pathway the alternative pathway does not require a rise of intracellular [Ca2+] and is insensitive to the effects of CsA. In this report we provide evidence for the involvement of T cell-stimulating factor (TSF)--a probably novel murine cytokine--in the alternative pathway of lymphokine production. It is shown that fixation of the AC with carbodiimide or treatment of the AC with UV light greatly reduces their capacity to induce (in combination with IL2) the synthesis of IFN-gamma by T cells. This function is restored by addition of TSF. Moreover, TSF alone (without IL2) in combination with fixed AC can induce the synthesis of substantial amounts of IFN-gamma. Furthermore, TSF in combination with IL2 can stimulate freshly isolated spleen cells to produce IFN-gamma. The target cell resides probably in the non-B cell, non-T cell population.
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PMID:Components of an antigen-/T cell receptor-independent pathway of lymphokine production. 190 19

T lymphocytes and monocytes were exposed to microgravity and activated to produce interleukin 2 and interleukin 1, respectively. When Jurkat T cells were triggered with monoclonal antibodies directed against the CD3/T cell receptor complex in the presence of THP-1 monocytes used as accessory cells, cell-to-cell contacts took place in microgravity leading to normal production of interleukin 2 and interleukin 1, as compared to ground controls. In contrast, when cells were individually stimulated by soluble substances including a protein kinase C activating phorbol ester, the production of interleukin 1 and interleukin 2 was dramatically inhibited during microgravity exposure. This result indicates that microgravity may affect the cellular target of phorbol ester.
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PMID:Inhibition of phorbol ester-induced cell activation in microgravity. 191 66

The phorbol ester TPA is a potent protein kinase C (PKC) activator and a cofactor in the activation of the human Jurkat leukemic T cell line. We have studied the implication of the PKC signaling pathway in the process of T cell activation by generating TPA resistant mutants of Jurkat. These mutants were obtained by recovery of cells that survived a growth arrest induced by TPA. Several cellular phenomena dependent on TPA were dramatically altered in the mutated cells. The mutants were unable to form homoaggregates upon TPA stimulation. Moreover, they did not produce interleukin-2 after activation through engagement of the T cell receptor, in the presence of TPA. These results suggest that the PKC signaling pathway activated by TPA is defective in these cells. In an attempt to define and locate the defect present in the mutants, we have analysed the biochemical properties of PKC, the cellular receptor of TPA. The increase in kinase activity and the translocation of the enzyme to the plasma membrane after stimulation by TPA appeared to be normal in the mutants. We hypothesize that a metabolic step, critical for the completion of T cell activation, distinct from protein kinase C, is impaired in the mutant cells.
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PMID:Isolation and characterization of a T lymphocyte mutant defective in the protein kinase C signal transduction pathway. 192 9

T cell receptor-CD3 complex (TCR-CD3)-mediated signal transduction was analyzed in HPB-ALL and Jurkat T cell lines. Both cell lines express high levels of TCR-CD3 complex on the cell surface, but provide different model systems for TCR-CD3 signaling in T cells. Jurkat responds with both inositol phosphate generation and intracellular Ca2+ mobilization after triggering of TCR-CD3, whereas TCR-CD3 triggering of HPB-ALL induces Ca2+ mobilization without detectable inositol phosphate generation. By employing a permeabilized cell system, we show that the HPB-ALL line expressed normal levels of Ca2(+)-induced phospholipase C activity. However, the TCR-CD3 on this cell line seems to be uncoupled from phospholipase C activation. In agreement with this result we also show, by analysis of protein kinase C-dependent phosphorylation of three distinct substrates, that TCR-CD3 in HPB-ALL is apparently uncoupled from protein kinase C activation. These findings may have implications for understanding signal-transducing pathways in T cells at various stages of differentiation.
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PMID:Signal transduction through the T cell receptor-CD3 complex. Evidence for heterogeneity in receptor coupling. 197 May 88

T cell activation induced via cross-linking of the T cell receptor (TcR) stimulates hydrolysis of phosphatidylinositol to the second messengers diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG is necessary for the activation and function of protein kinase C (PKC) which is suggested to play a key role in the cascade of signal transduction when translocated from the cytosol to the cell membrane. In this report, we investigated responses of resting vs. activated Ly-2+ and L3T4+ T lymphocytes in the presence of the PKC inhibitor H7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine]. H7 inhibited the induction of primary T cell proliferation, while interleukin 2 (IL 2) production was fully retained. The effect of the PKC inhibitor on primary T cells depended on the type of ligand interacting with the TcR: increasing doses of concanavalin A or of immobilized anti-CD3 monoclonal antibody (mAb), but not of anti-V beta 8 or of anti-TcR alpha/beta mAb, partly overcame the blockade, indicating a differential signaling compared to the former stimuli. The blockade of T cell proliferation by H7 was not due to an inhibition of PKC translocation, but occurred even 4-8 h after T cell induction and correlated with a significant reduction of IL 2 receptor (IL 2R) expression. In contrast, the mRNA levels of IL 2R and the cellular proto-oncogenes c-fos and c-myc were not affected. On activated T cells, H7 neither blocked proliferation nor IL2R expression. Consequently, H7 dissects the signal resulting in T cell proliferation from those governing the triggering of other T cell functions, i.e. IL 2 production, during primary responses of Ly-2+ or L3T4+ murine T lymphocytes.
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PMID:Dissection of signals controlling T cell function and activation: H7, an inhibitor of protein kinase C, blocks induction of primary T cell proliferation by suppressing interleukin (IL)2 receptor expression without affecting IL2 production. 206 May 74

T cell receptor signaling has been implicated in an intrathymic process of cell selection in which potentially harmful autoreactive precursors are deleted before they emigrate to the periphery. Recent work has shown that immature thymocytes undergo apoptosis, or programmed cell death, upon stimulation via the T cell antigen receptor, and it has been suggested that this mechanism may mediate deletion of the self-reactive clones during T cell development. Here we report that the accessory cell-derived T cell growth hormone interleukin-1 prevents T cell receptor-mediated thymocyte apoptosis by a mechanism that appears to involve protein kinase C activation. This effect may be relevant to the positive signaling that spares the appropriate precursors during the generation of functional T lymphocytes.
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PMID:Interleukin 1 inhibits T cell receptor-mediated apoptosis in immature thymocytes. 210 39

Stimulation of Jurkat T cells with antibodies against the T cell receptor/CD3 complex induces a rise in the intracellular concentration of Ca2+ within seconds. The inositol phosphate-dependent Ca2+ mobilization induced by OKT3 was completely abrogated when Jurkat cells were pretreated for 1 min with the phorbol 12-myristate 13-acetate TPA (10nM), a concentration which activates protein kinase C (PKC). The effects of TPA on the Ca2+ fluxes were insensitive to treatment of the cells with known PKC inhibitors (H-7 and staurosporin) under conditions where the PKC-mediated phosphorylation was blocked. Furthermore, another activator of PKC, mezerein, inhibited the Ca2+ signal induced by OKT3. This inhibition, however, could completely be reversed by pretreatment with H-7 or staurosporine. We conclude that the TPA-mediated inhibition of Ca2+ fluxes in Jurkat T cells largely acts through a PKC-independent pathway.
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PMID:Phorbol 12-myristate 13-acetate (TPA) blocks CD3-mediated Ca2+ mobilization in Jurkat T cells independently of protein kinase C activation. 214 52

The c-raf kinase has been shown to be activated following stimulation of several tyrosine kinase growth factor receptors. We examined changes in c-raf following engagement of the T cell receptor for antigen (TCR), a stimulus which activates both a non-receptor tyrosine kinase and protein kinase C (PKC). We found that activation of the T-cell receptor on the T cell hybridoma 2B4 causes a rapid and stoichiometric hyperphosphorylation of c-raf and an increase in c-raf-associated kinase activity. Phosphoamino acid analysis showed that the phosphorylation was entirely on serine residues. High-resolution phosphopeptide mapping showed the appearance of a single major new phosphopeptide with TCR stimulation. That phosphopeptide was shown to comigrate with the major new phosphopeptide induced in response to phorbol ester. When cells were depleted of PKC by pretreatment with high concentrations of phorbol ester, TCR stimulation was no longer capable of inducing c-raf-associated kinase activity. To determine whether activation of the tyrosine kinase alone would activate c-raf, we examined the 2B4 variant cell line FL.8. In response to Thy-1 stimulation, these cells activate the tyrosine kinase but not protein kinase C due to a deficiency in TCR eta chain expression. We found that in contrast to Thy-1 stimulation of 2B4 cells, stimulation of FL.8 cells does not lead to the induction of c-raf-associated kinase activity, although phorbol ester activates the kinase to an equivalent degree in both cells. We conclude that T cell receptor activation of c-raf occurs via phosphorylation by the serine/threonine kinase PKC. Activation of c-raf through PKC represents a mechanism distinct from that reported for tyrosine kinase growth factor receptors.
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PMID:T cell antigen receptor engagement stimulates c-raf phosphorylation and induces c-raf-associated kinase activity via a protein kinase C-dependent pathway. 217 Apr 13

We demonstrate here that T cell receptor for antigen (TCR)-triggered exocytosis in cytotoxic T lymphocytes (CTL) is not constitutive and is regulated through crosslinking of the TCR by antigen or monoclonal anti-TCR antibodies. Morphological and biochemical data using three different biochemical markers of granules and Percoll gradient fractionation analysis are presented, suggesting that TCR-triggered exocytosis is accompanied by the loss of granules from CTL and appearance of intragranular proteins and enzymatic activities in the incubation medium. The strict requirement for crosslinking of the TCR in exocytosis triggering could be bypassed by protein kinase C activators (phorbol esters or bryostatin I and II) acting in synergy with Ca2+ ionophores. It is shown that external Ca2+ is obligatory for both the TCR-triggered and for the PMA/A23187-triggered exocytosis, since Ca2+ chelators and divalent cations that compete with Ca2+ for A23187 can inhibit exocytosis of granules. These data suggest that Ca2+ from intracellular stores is not sufficient to support exocytosis in CTL. Ca2+ channel blockers and calmodulin antagonists significantly inhibited TCR-triggered exocytosis without affecting the basal level of secretion. The described results are consistent with a model in which exocytosis of granules in CTL is triggered by the crosslinking of TCR, transmembrane protein kinase C activation, and external Ca2+ translocation through CTL plasma membrane Ca2+ channels and modulation of activity of Ca2+, calmodulin-dependent enzymes, and cytoskeletal proteins.
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PMID:Antigen receptor-regulated exocytosis in cytotoxic T lymphocytes. 244 89


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