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 investigated the role of protein kinase C theta (PKCtheta) in the activation of the NF-kappaB cascade in primary human CD4(+) lymphocytes. Among six or so PKC isoforms expressed in T cells, only PKCtheta participates in the assembly of the supramolecular activation clusters at the contact site of the TCR with Ag. Signaling via both the TCR and CD28 is required for optimal activation of the multisubunit IkappaB kinase (IKK) complex in primary human T lymphocytes; this activation could be inhibited by a Ca(2+)-independent PKC isoform inhibitor, rottlerin. Moreover, endogenous PKCtheta physically associates with activated IKK complexes in CD3/CD28-costimulated primary CD4(+) T cells. The same set of stimuli also induced relocation of endogenous PKCtheta and IKKs to a GM1 ganglioside-enriched, detergent-insoluble membrane compartment in primary T cells. IKKs recruited to these lipid rafts were capable of phosphorylating a recombinant IkappaBalpha sustrate. Confocal microscopy further demonstrated that exogenously expressed PKCtheta and IKKss colocalize in the membrane of CD3/CD28-costimulated Jurkat T cells. Constitutively active but not kinase-inactive PKCtheta activated IKKbeta in Jurkat T cells. Expression of dominant-active PKCtheta also had stimulatory effects on the CD28 response element of the IL-2 promoter. Taken together, these data show that the activation of PKCtheta by the TCR and CD28 plays an important role in the assembly and activation of IKK complexes in the T cell membrane.
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PMID:The physical association of protein kinase C theta with a lipid raft-associated inhibitor of kappa B factor kinase (IKK) complex plays a role in the activation of the NF-kappa B cascade by TCR and CD28. 1112 Aug 19

Protein kinase C theta (PKC theta) is known to induce NF-kappa B, an essential transcriptional element in T cell receptor/CD28-mediated interleukin-2 production but also T cell survival. Here we provide evidence that PKC theta is physically and functionally coupled to Akt1 in this signaling pathway. First, T cell receptor/CD3 ligation was sufficient to induce activation as well as plasma membrane recruitment of PKC theta. Second, PKC theta selectively cooperated with Akt1, known to act downstream of CD28 co-receptor signaling, in activating a NF-kappa B reporter in T cells. Third, Akt1 function was shown to be required for PKC theta-mediated NF-kappa B transactivation. Fourth, PKC theta co-immunoprecipitated with Akt1; however, neither Akt1 nor PKC theta served as a prominent substrate for each other in vitro as well as in intact T cells. Finally, plasma membrane targeting of PKC theta and Akt1 exerted synergistic transactivation of the I-kappa B kinase beta/inhibitor of NF-kappa B/NF-kappa B signaling cascade independent of T cell activation. Taken together, these findings suggest a direct cross-talk between PKC theta and Akt1 in Jurkat T cells.
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PMID:Complex formation and cooperation of protein kinase C theta and Akt1/protein kinase B alpha in the NF-kappa B transactivation cascade in Jurkat T cells. 1141 May 91

Cognate interactions between CD154 (CD40 ligand, CD40L) on activated T cells and its receptor CD40 on various antigen-presenting cells are involved in thymus-dependent humoral immune responses and multiple other cell-mediated immune responses. We have studied the regulation of CD154 expression in human T cells after activation with anti-CD3 and anti-CD28 antibodies or after pharmacological activation of protein kinase C with phorbol 12-myristate 13-acetate, and the calcium ionophore ionomycin. Under these conditions, transcription of the CD154 gene was rapidly induced without requiring de novo protein synthesis. Pharmacological inhibitors of NF-kappaB activation down-regulated CD154 mRNA and protein levels. Cyclosporin A, an inhibitor of NF-AT activation, acted similarly, and the effects of both inhibitors were additive. A potential NF-kappaB binding site is present within the CD154 promoter at positions -1190 to - 1181. In electrophoretic mobility shift assays, this sequence was specifically bound by NF-kappaB present in nuclear extracts from activated T cells. Furthermore, in transient co-transfection of Jurkat T cells, p65 activated the transcription of a reporter construct containing a multimer of this NF-kappaB binding site. These observations demonstrate a role of NF-kappaB transcription factors in the regulation of CD40L expression in activated primary human T cells.
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PMID:NF-kappaB is involved in the regulation of CD154 (CD40 ligand) expression in primary human T cells. 1152 14

A novel polyunsaturated fatty acid (PUFA), beta-oxa 21:3n-3, containing an oxygen atom in the beta position, was chemically synthesized, and found to have more selective biological activity than the n-3 PUFA, docosahexaenoic acid (22:6n-3) on cells of the immune system. Although beta-oxa 21:3n-3 was very poor compared with 22:6n-3 at stimulating oxygen radical production in neutrophils, it was more effective at inhibiting human T lymphocyte proliferation (IC(50) of 1.9 vs 5.2 microM, respectively). beta-Oxa 21:3n-3 also inhibited the production of TNF-beta, IFN-gamma, and IL-2 by purified human T lymphocytes stimulated with PHA plus PMA, anti-CD3 plus anti-CD28 mAbs, or PMA plus A23187. Metabolism of beta-oxa 21:3n-3 via the cyclooxygenase and lipoxygenase pathways was not required for its inhibitory effects. Consistent with its ability to suppress T lymphocyte function, beta-oxa 21:3n-3 significantly inhibited the delayed-type hypersensitivity response and carrageenan-induced paw edema in mice. In T lymphocytes, beta-oxa 21:3n-3 inhibited the agonist-stimulated translocation of protein kinase C-betaI and -epsilon, but not -alpha, -betaII, or -theta to a particulate fraction, and also inhibited the activation of the extracellular signal-regulated protein kinase, but not c-Jun NH(2)-terminal kinase and p38. In contrast, 22:6n-3 had no effects on these protein kinase C isozymes. The increase in antiinflammatory activity and loss of unwanted bioaction through the generation of a novel synthetic 22:6n-3 analogue provides evidence for a novel strategy in the development of anti-inflammatory agents by chemically engineering PUFA.
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PMID:A novel long chain polyunsaturated fatty acid, beta-Oxa 21:3n-3, inhibits T lymphocyte proliferation, cytokine production, delayed-type hypersensitivity, and carrageenan-induced paw reaction and selectively targets intracellular signals. 1156 17

The novel protein kinase C (PKC) isoform, PKC theta, is selectively expressed in T lymphocytes and is a sine qua non for T cell antigen receptor (TCR)-triggered activation of mature T cells. Productive engagement of T cells by antigen-presenting cells (APCs) results in recruitment of PKC theta to the T cell-APC contact area--the immunological synapse--where it interacts with several signaling molecules to induce activation signals essential for productive T cell activation and IL-2 production. The transcription factors NF-kappa B and AP-1 are the primary physiological targets of PKC theta, and efficient activation of these transcription factors by PKC theta requires integration of TCR and CD28 costimulatory signals. PKC theta cooperates with the protein Ser/Thr phosphatase, calcineurin, in transducing signals leading to activation of JNK, NFAT, and the IL-2 gene. PKC theta also promotes T cell cycle progression and regulates programmed T cell death. The exact mode of regulation and immediate downstream substrates of PKC theta are still largely unknown. Identification of these molecules and determination of their mode of operation with respect to the function of PKC theta will provide essential information on the mechanism of T cell activation. The selective expression of PKC theta in T cells and its essential role in mature T cell activation establish it as an attractive drug target for immunosuppression in transplantation and autoimmune diseases.
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PMID:Protein kinase C(theta) in T cell activation. 1186 17

PKCtheta plays an essential role in activation of mature T cells via stimulation of AP-1 and NF-kappaB, and is known to selectively translocate to the immunological synapse in antigen-stimulated T cells. Recently, we reported that a Vav/Rac pathway which depends on actin cytoskeleton reorganization mediates selective recruitment of PKCtheta to the membrane or cytoskeleton and its catalytic activation by anti-CD3/CD28 costimulation. Because this pathway acted selectively on PKCtheta, we addressed here the question of whether the translocation and activation of PKCtheta in T cells is regulated by a unique pathway distinct from the conventional mechanism for PKC activation, i.e., PLC-mediated production of DAG. Using three independent approaches, i.e., a selective PLC inhibitor, a PLCgamma1-deficient T cell line, or a dominant negative PLCgamma1 mutant, we demonstrate that CD3/CD28-induced membrane recruitment and COOH-terminal phosphorylation of PKCtheta are largely independent of PLC. In contrast, the same inhibitory strategies blocked the membrane translocation of PKCalpha. Membrane or lipid raft recruitment of PKCtheta (but not PKCalpha) was absent in T cells treated with phosphatidylinositol 3-kinase (PI3-K) inhibitors or in Vav-deficient T cells, and was enhanced by constitutively active PI3-K. 3-phosphoinositide-dependent kinase-1 (PDK1) also upregulated the membrane translocation of PKCtheta;, but did not associate with it. These results provide evidence that a nonconventional PI3-K- and Vav-dependent pathway mediates the selective membrane recruitment and, possibly, activation of PKCtheta in T cells.
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PMID:Translocation of PKC[theta] in T cells is mediated by a nonconventional, PI3-K- and Vav-dependent pathway, but does not absolutely require phospholipase C. 1195 28

T-cell biological responses appear to involve the complex interaction of T-cell surface receptors, intracellular signaling molecules and the cytoskeleton. Both the serine/threonine protein kinase families protein kinase C (PKC) and protein kinase B or RAC-PK (AKT/PKB) have been implicated in signal transmission leading to activation, differentiation as well as cellular survival of T-lymphocytes. The PKC gene family consists of nine diverse isotypes (PKC alpha, beta, gamma, delta, epsilon, xi, eta, theta; and iota), the AKT/PKB gene family includes three kinases (AKT1/PKB alpha, AKT2/PKB beta, AKT3/PKB gamma). Here, we attempt to summarize the regulation as well as downstream signaling pathways of PKC and AKT/PKB isotypes, that may act additive in TCR/CD28 induced proliferation and survival of peripheral CD4+ T-lymphocytes.
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PMID:Protein kinase C and AKT/protein kinase B in CD4+ T-lymphocytes: new partners in TCR/CD28 signal integration. 1204 76

The signaling pathways that lead to the localization of cellular protein to the area of interaction between T cell and antigen-presenting cell and the mechanism by which these molecules are further sorted to the peripheral supramolecular activation cluster or central supramolecular activation cluster regions of the immunologic synapse are poorly understood. In this study, we investigated the functional involvement of CD28 costimulation in the T cell receptor (TCR)-mediated immunologic synapse formation with respect to protein kinase C (PKC)theta; localization. We showed that CD3 crosslinking alone was sufficient to induce PKC theta; capping in naive CD4(+) T cells. Studies with pharmacologic inhibitors and knockout mice showed that the TCR-derived signaling that drives PKC theta; membrane translocation requires the Src family kinase, Lck, but not Fyn. In addition, a time course study of the persistence of T cell molecules to the immunologic synapse indicated that PKC theta;, unlike TCR, persisted in the synapse for at least 4 h, a time that is sufficient for commitment of a T cell to cell division. Finally, by using TCR-transgenic T cells from either wild-type or CD28-deficient mice, we showed that CD28 expression was required for the formation of the mature immunologic synapse, because antigen stimulation of CD28(-) T cells led to a diffuse pattern of localization of PKC theta; and lymphocyte function-associated antigen-1 in the immunologic synapse, in contrast to the central supramolecular activation cluster localization of PKC theta; in CD28(+) T cells.
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PMID:CD28 plays a critical role in the segregation of PKC theta within the immunologic synapse. 1207 22

Lipid rafts are important signaling platforms in T cells. Little is known about their properties in human CD8(+) T cells. We studied polarization of lipid rafts by digital immunofluorescence microscopy in primary human T cells, using beads coated with anti-CD3 and anti-CD28 mAbs (CD3/28 beads). Unlike CD4(+) T cells, CD8(+) T cells did not polarize lipid rafts when stimulated with CD3/28 beads, when the anti-CD28 antibody was substituted with B7.2Ig, or if an anti-CD8 antibody was added to the CD3/28 beads. This phenomenon was also observed in human antigen-specific CD8(+) T cells. On stimulation with CD3/28 beads, the T cell antigen receptor clustered at the cell/bead contact area in both CD4(+) and CD8(+) T cells. Examination of lipid rafts isolated by sucrose density gradient centrifugation revealed the constitutive expression of p(56)Lck in the raft fractions of unstimulated CD8(+) T cells, whereas p(56)Lck was recruited to the raft fraction of CD4(+) T cells only after stimulation with CD3/28 beads. Stimulation with CD3/28 beads induced marked calcium flux, recruitment of PKC-theta and F-actin to the cell/bead contact site, and similar proliferation patterns in CD4(+) and CD8(+) T cells. Thus, polarization of lipid rafts is not essential for early signal transduction events or proliferation of human CD8(+) lymphocytes. It is possible that the lower stringency of CD8(+) T cell activation obviates a requirement for raft polarization.
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PMID:Human CD8+ T cells do not require the polarization of lipid rafts for activation and proliferation. 1241 50

The Nef protein of Simian immunodeficiency virus (SIV) associates with multiple T lymphocyte signaling proteins, including the T cell receptor (TCR) zeta chain. We demonstrate here that these interactions are conserved and highly specific. Nefs derived from genetically diverse strains of SIV (SIV(mac)239, SIV(smm)PBj, and SIV(smm)DeltaB670) all interacted with TCR zeta on two separate domains, referred to as SIV Nef interaction domains (SNIDs), as examined in both yeast two-hybrid and glutathione-S-transferase (GST) fusion protein pull-down assays. Multiple HIV-1 Nefs were examined and none interacted with TCR zeta. In contrast, HIV-2(UC1) Nef, similar to SIV Nef, interacted with TCR zeta on two domains, although only the SIV Nefs potently reduced cell-surface expression of the TCR/CD3 complex in T cells. In addition, we examined the abilities of SIV, HIV-2, and HIV-1 Nefs to interact with the cytoplasmic domains of other signaling molecules including CD3epsilon, CD3gamma, and FcepsilonRIgamma, which also contain YxxL motifs, and determined that SIV and HIV-2 Nefs interacted only with TCR zeta, whereas HIV-1 Nef did not interact with any signal-transducing cytoplasmic domain examined. Last, to gain further insight into the mechanism by which Nef down-modulates the TCR/CD3 complex, we mutated or deleted regions on Nef involved in endocytosis, localization of Nef to the plasma membrane, interaction with cellular kinases, or that were conserved among multiple strains of SIV. Mutation of the myristoylation site and a conserved region surrounding a putative PKC phosphorylation site were the only mutations that abrogated Nef-mediated down-modulation of the TCR/CD3 complex. These findings demonstrate there is a spectrum of associations between SIV, HIV-2, and HIV-1 Nefs, and the TCR/CD3 complex, and suggest that down-modulation of the TCR/CD3 complex occurs via association with subsets of cellular proteins that are different from those involved in CD4 and CD28 down-modulation.
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PMID:The conserved process of TCR/CD3 complex down-modulation by SIV Nef is mediated by the central core, not endocytic motifs. 1242 20


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