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 present study has examined the role of IL-2 and IL-4 in the regulation of different kinase pathways for the generation of alphaCD3-induced activated killer cells, CD3-AK. It has previously been shown that the IL-2 promoted CD3-AK cell response is mediated through a PKC (protein kinase C)-dependent pathway, which is susceptible to PKC inhibitors and resistant to inhibitors of PTK (protein tyrosine kinase), and that IL-4 synergized with IL-2 to induce CD3-AK cells. However, the IL-4-promoted CD3-AK cell response was PKC-independent as assessed by its resistance to PKC inhibitors. These findings suggest a dichotomy in the pathways leading to CD3-AK cell generation. To further determine whether IL-4 mediated a different kinase pathway to activate the T cells, we studied its effect on protein tyrosine phosphorylation. IL-4 up-regulated protein tyrosine phosphorylation in CD3-AK cells in a dose-dependent fashion, and resulted in increased levels of a number of phosphorylated proteins. Of particular note was the increase of tyrosine phosphorylated p56(lck) and p59(fyn) in CD3-AK cells. The changes in global protein tyrosine phosphorylation were correlated with the up-regulation by IL-4 of CD3-AK cell cytolytic activity, and the production of granzyme A. alphaIL-4 specifically blocked all the effects which were induced by IL-4. The PTK inhibitor genistein inhibited the IL-4-augmented cytolytic activity of CD3-AK cells as well as the IL-4-induced augmentation of protein tyrosine phosphorylation to the basal level of CD3-AK cells cultured in IL-2 alone. Consistent with a dichotomy in pathways for IL-2- and IL-4-mediated CD3-AK generation, genistein had no effect on the generation of CD3-AK cells cultured in IL-2 alone. Thus while PKC is primarily involved in the generation of IL-2-promoted CD3-AK cells, PTK appears to be required for the regulation of IL-4-promoted CD3-AK response.
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PMID:IL-2 and IL-4 mediate through two distinct kinase pathways for the activation of alphaCD3-induced activated killer cells. 895 13

We have recently described the cDNA and predicted protein structure of a natural soluble CD4 ligand, IL-16. IL-16 is chemotactic for CD4+ T cells and induces functional IL-2 receptors in CD4+ T cells. The binding of IL-16 to CD4 results in activation of p56(lck), whose adaptor function is essential for the chemotactic response. Subsequently, increases in intracellular Ca2+ and phosphatidylinositol 1,4,5-trisphosphate occur, as does translocation of protein kinase C from cytosol to membrane. Because of the similarities between these signals and functions and those noted for the CD4 ligand HIV-1 gp120, we investigated the potential regulatory effects of IL-16 on CD3/TCR-mediated lymphocyte activation. Preincubation of human T cells with IL-16 up to 24 h before activation with plate-bound anti-CD3 Abs reduced T cell activation by 80%, as monitored by IL-2R expression and [3H]thymidine uptake. If IL-16 was added following anti-CD3 activation, no suppression was noted. The suppressive effects of preincubation with IL-16 were not rescued by the addition of rIL-2 and were not the result of priming for anti-CD3-induced apoptosis. In addition, IL-16 had no effect on surface expression of CD3 or CD4. However, IL-16 did reduce the magnitude of the anti-CD3-induced intracellular Ca2+ increase. These studies indicate that while the interaction of CD4 with its natural ligand, IL-16, results in Ag-independent chemotaxis and IL-2R expression, this pro-inflammatory state is associated with subsequent transient inhibition of responsiveness via the CD3/TCR complex.
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PMID:IL-16 inhibition of CD3-dependent lymphocyte activation and proliferation. 895 68

The CD4 molecule acts as a receptor for class II MHC molecules to stabilize Ag recognition by the TCR and as a high affinity receptor for HIV-1. In this study, we investigated the effect of oxidative stress on the level of CD4 expression on cultured peripheral blood T lymphocytes (PBL blasts). As previously reported, we observed that the surface CD4 was down-regulated by PMA. Unexpectedly, treatment of PBL blasts with hydrogen peroxide (H2O2) or a sulfhydryl oxidative reagent, diamide, almost completely inhibited PMA-induced CD4 down-regulation, although these oxidants per se did not affect the level of CD4 expression. We next assessed the serine phosphorylation of CD4, which is reported to be an indispensable process for PMA-induced CD4 endocytosis. PMA could induce the serine phosphorylation even in the presence of oxidants. We also found that these oxidants had an additive effect on PMA-induced dissociation between CD4 and p56(lck), which is known to be another necessary step for CD4 endocytosis. These results indicate that in T cells, oxidants inhibit protein kinase C-mediated CD4 down-regulation due to perturbing a signaling process other than the above two steps, implying that oxidative stress may tune the functions of CD4+ T cells and their susceptibility to HIV-1 through the control of CD4 expression.
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PMID:Inhibition of protein kinase C-mediated CD4 down-regulation by oxidative stress in T lymphocytes. 895 81

Different classes of protein kinase inhibitors for protein kinase C, cAMP-dependent protein kinase or protein tyrosine kinases have been studied for their effect on phospholipid metabolism. The results show that among the compounds studied, only 4'-aminohydroxyflavone (AHF), previously described as a specific inhibitor of the protein tyrosine kinase p56(lck), markedly increased phosphatidylserine synthesis in Jurkat T cells. The biosyntheses of phosphatidylcholine and phosphatidylethanolamine were not affected. Also, the synthesis of phospholipids from tritium-labeled fatty acid as precursor was left unchanged by the p56(lck) inhibitor. The decreased phosphatidylserine synthesis induced when triggering the CD3-TCR complex was impaired by AHF, suggesting that p56(lck) could be implicated in the regulation of the serine-base exchange enzyme system. Direct evidence for the participation of p56(lck) in the regulation of the serine-base exchange enzyme system was obtained by using p56(lck)-deficient Jurkat cells (J.CaM 1.6) in which the basal base exchange activity was markedly increased and on the other hand AHF had no effect. In addition, transfection of J.Cam 1.6 cells with p56(lck)-cDNA allowed recovery of the AHF activity.
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PMID:The protein tyrosine kinase p56(lck) regulates the serine-base exchange activity in Jurkat T cells. 908 83

It is controversial whether altered levels of TCR/CD3-associated signalling molecules play a role in the T-cell dysfunction of cancer patients. In multiple myeloma (MM), peripheral blood T (PBT) lymphocytes are functionally impaired by prolonged exposure to tumour cells, and so we investigated the organization of the TCR/CD3-associated signal transduction machinery. The aim of this study was two-fold: first, to investigate the levels of CD3zeta, p56(lck), p59(fyn), ZAP-70, protein kinase C-alpha (PKC-alpha) and phospholipase C-gamma (PLC-gamma) in MM PBT cells; second, to determine whether levels of expression were correlated with clinical or prognostic factors. Forty-four MM patients were studied and 25 age-matched normal donors served as controls. On average, PKC-alpha was the only significantly decreased (P<0.001) signalling molecule, whereas levels of CD3zeta, p56(lck), p59(fyn), PLC-gamma and ZAP-70 were not statistically different. However, there was wide variation between individual patients, and levels for each single protein also varied. A 75% or greater decrease in protein expression was observed, ranging from 8% (p59(fyn)) to 68% (PCK-alpha) of MM patients. When patients were grouped according to the cut-off values of prognostic factors such as the serum levels of C reactive protein (CRP), beta2-microglobulin (beta2M), neopterin (NPT) and the labelling index (LI%) of bone marrow (BM) plasma cells, the only difference observed was the lower PKC-alpha expression in patients with high serum NPT values. None of the T-cell signalling molecule levels was affected by the duration of tumour exposure, calculated on the number of years and/or months that had elapsed since diagnosis, or by disease status. In conclusion, there was a significant decrease of PCK-alpha in MM T cells; however, neither this decrease nor the heterogenous levels of the other T-cell signalling molecules were clearly correlated with prognosis, duration of tumour exposure, and disease status.
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PMID:Distribution of T-cell signalling molecules in human myeloma. 921 82

Recently, TAP42 was isolated as a high copy suppressor of sit4-, a yeast phosphatase related to protein phosphatase 2A (PP2A). TAP42 is related to the murine alpha4 protein, which was discovered independently by its association with Ig-alpha in the B cell receptor complex. Herein we show that a glutathione S-transferase (GST)-alpha4 fusion protein bound the catalytic subunit (C) of human PP2A from monomeric or multimeric preparations of PP2A in a "pull-down" assay. In an overlay assay, the GST-alpha4 protein bound to the phosphorylated and unphosphorylated forms of C that were separated in two-dimensional gels and immobilized on filters. The results show direct and exclusive binding of alpha4 to C. This is unusual because all known regulatory B subunits, or tumor virus antigens, bind stably only to the AC dimer of PP2A. The alpha4-C form of PP2A had an increased activity ratio compared with the AC form of PP2A when myelin basic protein phosphorylated by mitogen-activated protein kinase and phosphorylase a were used as substrates. Recombinant alpha4 cleaved from GST was phosphorylated by p56(lck) tyrosine kinase and protein kinase C. A FLAG-tagged alpha4 expressed in COS7 cells was recovered as a protein containing phosphoserine and coimmunoprecipitated with the C but not the A subunit of PP2A. Treatment of cells with rapamycin prevented the association of PP2A with FLAG-alpha4. The results reveal a novel heterodimer alpha4-C form of PP2A that may be involved in rapamycin-sensitive signaling pathways in mammalian cells.
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PMID:B cell receptor-associated protein alpha4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. 938 Jun 85

An increasing number of independent studies indicate that the atypical protein kinase C (PKC) isoforms (aPKCs) are critically involved in the control of cell proliferation and survival. The aPKCs are targets of important lipid mediators such as ceramide and the products of the PI 3-kinase. In addition, the aPKCs have been shown to interact with Ras and with two novel proteins, LIP (lambda-interacting protein; a selective activator of lambda/iotaPKC) and the product of par-4 (a gene induced during apoptosis), which is an inhibitor of both lambda/iotaPKC and zetaPKC. LIP and Par-4 interact with the zinc finger domain of the aPKCs where the lipid mediators have been shown to bind. Here we report the identification of p62, a previously described phosphotyrosine-independent p56(lck) SH2-interacting protein, as a molecule that interacts potently with the V1 domain of lambda/iotaPKC and, albeit with lower affinity, with zetaPKC. We also show in this study that ectopically expressed p62 colocalizes perfectly with both lambda/iotaPKC and zetaPKC. Interestingly, the endogenous p62, like the ectopically expressed protein, displays a punctate vesicular pattern and clearly colocalizes with endogenous lambda/iotaPKC and endogenous zetaPKC. P62 colocalizes with Rab7 and partially with lamp-1 and limp-II as well as with the epidermal growth factor (EGF) receptor in activated cells, but not with Rab5 or the transferrin receptor. Of functional relevance, expression of dominant negative lambda/iotaPKC, but not of the wild-type enzyme, severely impairs the endocytic membrane transport of the EGF receptor with no effect on the transferrin receptor. These findings strongly suggest that the aPKCs are anchored by p62 in the lysosome-targeted endosomal compartment, which seems critical for the control of the growth factor receptor trafficking. This is particularly relevant in light of the role played by the aPKCs in mitogenic cell signaling events.
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PMID:Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62. 956 25

TCR down-regulation plays an important role in modulating T cell responses both during T cell development and in mature T cells. Down-regulation of the TCR is induced by engagement of the TCR by specific ligands and/or by activation of protein kinase C (PKC). We report here that ligand- and PKC-induced TCR down-regulation is mediated by two distinct, independent mechanisms. Ligand-induced TCR down-regulation is dependent on the protein tyrosine kinases p56(lck) and p59(fyn) but independent of PKC and the CD3gamma leucine-based (L-based) internalization motif. In contrast, PKC-induced TCR down-regulation is dependent on the CD3gamma L-based internalization motif but independent of p56(lck) and p59(fyn). Finally, our data indicate that in the absence of TCR ligation, TCR expression levels can be finely regulated via the CD3gamma L-based motif by the balance between PKC and serine/threonine protein phosphatase activities. Such a TCR ligation-independent regulation of TCR expression levels could probably be important in determining the activation threshold of T cells in their encounter with APC.
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PMID:Two distinct pathways exist for down-regulation of the TCR. 964 32

The cAMP-responsive element-binding protein (CREB) transcription factor is required for normal T cell activation following stimulation through the T cell antigen receptor (TCR). CREB is present in resting T cells in an unphosphorylated and inactive state. TCR engagement results in the rapid phosphorylation of CREB on Ser133 and its concomitant activation. In the studies described in this report, we have investigated the signaling pathway(s) that are responsible for CREB activation in normal T cells. Using pharmacological agonists, we show that protein kinase C (PKC)-, calcium/calmodulin-, and protein kinase A-dependent pathways are each capable of independently eliciting CREB phosphorylation in T cells and thymocytes. Pharmacological inhibitor studies demonstrated that the PKC-mediated signaling pathway is required for TCR-mediated activation of CREB. In contrast, inhibitors of protein kinase A and calmodulin kinases had no effect on CREB phosphorylation following TCR cross-linking. T cells lacking the p56(lck) tyrosine kinase failed to phosphorylate CREB in response to TCR engagement. Overexpression of dominant-negative mutant Ras and Raf-1 proteins in Jurkat T cells abolished TCR-mediated CREB phosphorylation, whereas overexpression of the RSK2 serine/threonine kinase significantly potentiated TCR-mediated CREB phosphorylation. Taken together, these experiments are consistent with a model in which TCR engagement leads to the rapid phosphorylation and activation of CREB via a signaling pathway involving the activation of p56(lck), PKC, Ras, Raf-1, MEK, and RSK2. Given the importance of CREB phosphorylation in normal T cell activation, this pathway may be an attractive target for the development of novel immunosuppressive agents.
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PMID:A protein kinase C-, Ras-, and RSK2-dependent signal transduction pathway activates the cAMP-responsive element-binding protein transcription factor following T cell receptor engagement. 971 19

The T cell receptor (TCR) is internalized following activation of protein kinase C (PKC) via a leucine (Leu)-based motif in CD3gamma. Some studies have indicated that the TCR is recycled back to the cell surface following PKC-mediated internalization. The functional state of recycled TCR and the mechanisms involved in the sorting events following PKC-induced internalization are not known. In this study, we demonstrated that following PKC-induced internalization, the TCR is recycled back to the cell surface in a functional state. TCR recycling was dependent on dephosphorylation of CD3gamma, probably mediated by the serine/threonine protein phosphatase-2A, but independent on microtubules or actin polymerization. Furthermore, in contrast to ligand-mediated TCR sorting, recycling of the TCR was independent of the tyrosine phosphatase CD45 and the Src tyrosine kinases p56(Lck) and p59(Fyn). Studies of mutated TCR and chimeric CD4-CD3gamma molecules demonstrated that CD3gamma did not contain a recycling signal in itself. In contrast, the only sorting information in CD3gamma was the Leu-based motif that mediated lysosomal sorting of chimeric CD4-CD3gamma molecules. Finally, we found a correlation between the phosphorylation state of CD3gamma and T cell responsiveness. Based on these observations a physiological role of CD3gamma and TCR cycling is proposed.
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PMID:The phosphorylation state of CD3gamma influences T cell responsiveness and controls T cell receptor cycling. 972 47


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