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)

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

Transmembrane signaling of normal human T cells was explored with mAbs directed at TCR, CD2, CD4, CD5, or CD8 antigens and highly purified CD4+ T cells and CD8+ T cells. Our experiments explicitly show that: (a) crosslinkage of TCR with the CD2 antigen, and not independent crosslinking of TCR and of CD2 antigen or crosslinking of either protein with the CD4 or CD8 antigen induces significant proliferation independent of co-stimulatory signals (e.g., accessory cells, recombinant lymphokines, or tumor promoter), (b) F(ab')2 fragments of mAb directed at the TCR and F(ab')2 anti-CD2, crosslinked with F(ab')2 fragments of rabbit anti-mouse IgG, promote the proliferation of highly purified T cells, (c) a prompt and sustained increase in intracellular free Ca2+ concentration results from crosslinkage of TCR with the CD2 antigen, (d) T cell proliferation induced by this novel approach is curtailed by EGTA and by direct or competitive inhibitors of PKC, (e) crosslinkage of TCR with the CD2 antigen results in the transcriptional activation and translation of the gene for IL-2 and in the expression of IL-2 receptor alpha (CD25), (f) anti-CD25 mAbs inhibit T cell proliferation initiated by crosslinkage of TCR with the CD2 antigen, and recombinant IL-2 restores the proliferative response. Our first demonstration that crosslinkage of TCR with the CD2 antigen induces proliferation of normal human CD4+ T cells and CD8+ T cells, in addition to revealing a novel activation mechanism utilizable by the two major subsets of T cells, suggest that the CD2 antigen might be targeted for the regulation of antigen-specific T cell immunity (e.g., organ transplantation).
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PMID:A novel model for antigen-dependent activation of normal human T cells. Transmembrane signaling by crosslinkage of the CD3/T cell receptor-alpha/beta complex with the cluster determinant 2 antigen. 197 76

Ag-dependent activation of human T cells results in high level expression of class II MHC molecules. As part of this process, Ag recognition by TCR generates a series of second signals including protein kinase C, tyrosine kinase, and Ca2+ mobilization. To investigate the role of these second messengers in class II MHC expression, purified T cells were first stimulated by PMA, ionomycin, OKT3 accompanied by IL-2, or the mitogenic anti-CD2 antibodies T112 and T113 and were then stained with FITC-conjugated anti-class I and -class II MHC antibodies for analysis by flow cytometry. OKT3 and IL-2 induced optimal expression of HLA-DR (DR) on 70% of T cells with high density. Despite their high mitogenicity, induction of class II MHC expression by PMA, even with co-stimulation by ionomycin, was reduced to less than 20% of T cells, with an intensity 50-fold lower than in OKT3/IL-2-stimulated T cells. Furthermore, PMA inhibited class II MHC expression by OKT3/IL-2-stimulated T cells in a dose-dependent manner and additional stimuli, such as IL-1, IL-4, IFN-gamma, TCR cross-linkers, or monocytes, did not restore class II MHC expression by PMA-activated T cells. DR beta mRNA analysis showed that the low induction of class II molecules by PMA extends to the transcriptional level. Interestingly, anti-T112 and anti-T113 induced not only proliferation of T cells but also DR expression on more than 90% of T cells. These results indicate that transduction of a specific signal, probably selective phosphorylation of the CD3 molecule, contributes to class II MHC induction in the process of T cell activation.
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PMID:Selective signal transduction through the CD3 or CD2 complex is required for class II MHC expression by human T cells. 197 84

The molecular pathways that are responsible for delivering the proliferative signals from the cell surface to the nucleus in T lymphocytes are still unresolved, but recent data implicates protein kinase C (PKC) involvement in the TCR signaling pathway. To further address the role of PKC in T cell activation, the effects of high level expression of the PKC-gamma isoenzyme in murine CTL clones were examined. Unlike the parental cells that required periodic Ag stimulation for cell activation and growth, cells expressing a retrovirally transduced PKC-gamma gene propagated in culture independent of the need for Ag stimulation, although maintaining identical functional specificity to the parental CTL. Constitutive PKC-gamma expression may therefore mimic physiologic PKC activation, thereby abrogating the requirement for TCR-Ag interaction in T cell activation.
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PMID:Retroviral transduction of protein kinase C-gamma into cytotoxic T lymphocyte clones leads to immortalization with retention of specific function. 199 61

The protein kinase C activator phorbol 12-myristate 13-acetate (TPA) augments the level of cytoplasmic mRNA for cytoskeletal actin and the beta chain of the T cell antigen receptor (TCR beta) in peripheral blood lymphocytes. Calcium ionophore A23187 has an antagonistic effect on these increases. The immunosuppressive drug cyclosporin A blocked both positive and negative effects of A23187 without affecting those of TPA. TPA-mediated increases in cytoplasmic RNA for both genes can occur when transcription is blocked with actinomycin D and no increase is observed in the corresponding total cellular RNA. Activation of protein kinase C can thus mediate the accumulation of these mRNAs by a post-transcriptional mechanism.
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PMID:Post-transcriptional regulation of cytoskeletal actin and T lymphocyte receptor beta chain mRNA by phorbol ester. 200 7

CD6 (T12) is a 130-kDa glycoprotein present on the surface of human T cells. Previously, we demonstrated that the anti-T12 and anti-2H1 monoclonal antibodies recognized different epitopes on CD6, and both were capable of transducing activation signals to T cells. Anti-T12 augmented suboptimal signaling via the TCR/CD3 complex and directly activated separated CD4+ but not CD8+ cells. Structural characterization of CD6 revealed that it contained intrachain disulfide bonds, was N-glycosylated, and in activated cells was phosphorylated on serine. Given the functional significance of CD6 and its involvement in signaling via CD3 and CD2 pathways, we examined in detail the biosynthesis, structural characteristics, and phosphorylation properties of this receptor-like molecule. These studies demonstrate that the nascent CD6 polypeptide on both T cells and thymocytes in 88 kDa, and the immature N-glycosylated form is 110 kDa. After maturation of N-linked glycan and addition of sulfated O-linked oligosaccharide, CD6 appears on the cell surface as a molecule of 130 kDa. CD6 is phosphorylated in resting cells and can be hyperphosphorylated when stimulated by phorbol 12-myristate 13-acetate, indicating that it may participate in the major common signaling pathway mediated through protein kinase C. Concanavalin A-activated cells are phosphorylated at an additional site(s) on the molecule and cannot be hyperphosphorylated with phorbol 12-myristate 13-acetate. These physical features reveal additional clues about the physiological role of CD6 and its mechanism of signal transduction and strongly suggest that CD6 represents a physiologically important membrane receptor involved in T cell activation.
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PMID:Biosynthesis and post-translational modification of CD6, a T cell signal-transducing molecule. 201 20

Ligation of the TCR after interaction of a CTL with a relevant target cell results in a change in CTL shape with reorientation and secretion of cytoplasmic granules. Secretion can be induced by treating CTL with the combination of a phorbol ester to activate protein kinase C and ionomycin to increase the intracellular Ca2+ concentration by ion-selective permeabilization of both the plasma membrane and internal Ca2+ storage depots. Treatment of cloned murine CTL with PMA induced a change in cell shape without movement of cytoplasmic granules, whereas increased intracellular [Ca2+] after treatment with ionomycin resulted in granule movement without shape change. Granule movement induced by ionomycin did not lead to secretion in the absence of PMA. Direct activation of the TCR resulted in increased intracellular Ca2+ predominately from influx of extracellular Ca2+ with a substantially smaller contribution from release of Ca2+ from internal stores. By independently inhibiting either component of the TCR-initiated increase in intracellular Ca2+, it was determined that both sources of Ca2+ were required for granule movement and secretion. Thus, increases in intracellular Ca2+ concentration mediated by these two sources appear not to be functionally equivalent. Taken together, these results indicate that the CTL functional response that normally occurs after interaction with an antigenically relevant target cell is regulated by three independent signals.
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PMID:Three intracellular signals for cytotoxic T lymphocyte-mediated killing. Independent roles for protein kinase C, Ca2+ influx, and Ca2+ release from internal stores. 202 68

The present study has characterized two sets of alpha CD3-induced activated killer cells (CD3-AK). A 2 to 4-h 51Cr release assay or triton-treated 125IUdR release assay demonstrated that CD3-AK cultured in the continuous presence of alpha CD3 (CD3-AK+) mediated fast lysis. A 20-h 51Cr or 125I-deoxyuridine release assay demonstrated that CD3-AK cultured in the absence of alpha CD3 (CD3-AK-) mediated slow lysis. Activating the TCR-CD3 complex of CD3-AK- cells with alpha CD3 for 2 h enabled the killer cells to mediate fast lysis. The activation process was inhibited by H-7, a protein kinase C (PKC) inhibitor. Conversely, removal of alpha CD3 from CD3-AK+ cell cultures for 24 h resulted in almost complete loss of the ability of CD3-AK+ cells to mediate fast lysis, but they still retained the ability to mediate slow lysis. It appeared that constant perturbation of CD3 by alpha CD3 maintained the CD3-AK+ cells in an active state, and thus, they were able to mediate fast lysis. On the other hand, activation by a 2-h incubation with PMA could convert the noncytolytic CD3-AK- cells to be cytolytic in slow lysis and to augment the slow lytic reactions mediated by CD3-AK- cell with low cytolytic activity. These results were confirmed by triton-treated 125IUdR release assay which could detect early DNA-release. Thus it appeared that activation of CD3-AK cells with T cell activation signals that bypassed TCR (such as PMA) could induce slow lysis. In the effector phase of lytic reactions, the fast lytic reaction was relatively resistant to inhibition by H-7, whereas the slow lytic reaction was susceptible to H-7 inhibition, indicating that fast lysis was PKC independent and slow lysis was PKC dependent. It was further found that H-7 inhibition was at an early stage of slow lysis, suggesting that a PKC dependent activation process preceded the PKC independent lytic process. These findings indicated that the CD3-AK- cells were in a less activated state which required further activation to turn on their lytic machinery to initiate the lytic reaction.
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PMID:Anti-CD3 antibody-induced activated killer cells subsets of killer cells that mediate fast or slow lytic reactions. 214 18

Differentiation of bone-marrow-derived precursor cells into mature mouse T lymphocytes occurs in the thymus and involves sequential interactions with MHC-positive hemopoietic and epithelial stromal cells. To study the in vitro molecular mechanisms at play during the lympho-epithelial cell adhesion, we derived thymic stromal cell lines which were shown to possess cytokeratin filaments and tight junctions. These mouse thymic epithelial (MTE) cell lines did not express the classical hemopoietic stromal cell surface markers (i.e. LFA-1, Mac-1, and CD45) but expressed ICAM-1, NCAM, J11d, CD44, and MHC molecules. A quantitative cell adhesion assay was used to evaluate the interaction of various lymphoid cell subsets with MTE cells. Two cell interaction patterns could be defined: first, a rapid adhesion of a fraction of CD4+CD8+ and of a few CD4-CD8- immature thymocytes to MTE cells was observed at 4 degrees C. The CD8 molecule was shown to be partially involved in this initial contact. The strength of adhesion between MTE cells and distinct thymocyte subsets was evaluated and found to be maximal with neonatal thymocytes. Second, a temperature-dependent adhesion step characterized by a rapid and active stabilization of the interaction of MTE cells with 20% of CD4+CD8+CD3low thymocytes was seen, followed by a more progressive de-adhesion step. This active process of engagement was highly LFA-1-dependent, involved the CD4 and CD8 molecules, and required protein kinase C activation and cytoskeletal integrity. The results are consistent with the involvement of LFA-1 in a transient and regulated cell adhesion under the control of the TCR-CD3 complex that progressively appears on maturing cells. This phenomenon might contribute to the selection of a subset of immature thymocytes by epithelial cells occurring during the process of maturation of these cells.
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PMID:Mouse thymic epithelial cell lines interact with and select a CD3lowCD4+CD8+ thymocyte subset through an LFA-1-dependent adhesion--de-adhesion mechanism. 215 May 94

Increases in the cAMP level are often inhibitory in mature T lymphocytes and may be involved in the development of tolerance to self Ag. In this report, agents inducing an increase in the cAMP level by independent mechanisms were found to stimulate DNA fragmentation, characteristic of a suicide program known as apoptosis, in isolated thymocytes. Data obtained with cAMP analogs known to act synergistically to stimulate protein kinase A suggested that the latter directly mediated endonuclease activation. Agents previously shown to stimulate protein kinase C and to inhibit Ca2(+)-dependent, TCR-mediated thymocyte apoptosis, including IL-1, also blocked both DNA fragmentation and cell death in response to cAMP, suggesting interactions ("cross-talk") between the two protein kinase systems. As it has been proposed that apoptosis mediates negative cell selection in the thymus, our results indicate that cAMP may play a role in the development of functional mature T lymphocytes.
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PMID:Agents that elevate cAMP stimulate DNA fragmentation in thymocytes. 216 10


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