Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to investigate the influence of protein kinase C (PKC) alpha and beta on the TCR-CD28-stimulated protein kinase cascades participating in regulation of IL-2 gene transcription and secretion. Inhibition of the synthesis of PKCalpha and beta by specific phosphorothioate-modified antisense oligonucleotides (ODN) resulted in suppression of phosphorylation and activation of Raf-1, mitogen-activated extracellular-regulated kinase kinases and extracellular-regulated kinases in stimulated Jurkat T cells. Furthermore, a marked reduction of IkappaB kinase-alpha-catalyzed IkappaBalpha phosphorylation was observed in both PKCalpha- and beta-specific antisense oligonucleotide-treated cells. In sharp contrast, TCR-CD28-stimulated phosphorylation and activation of the Jun-N-terminal kinase (JNK) cascade was specifically suppressed upon treatment with PKCbeta-specific antisense ODN, suggesting that PKCbeta was a specific upstream regulator of the JNK protein kinase cascade. Significant inhibition of high-affinity NF-AT binding and transactivation, IL-2 gene expression, reduction of IL-2 mRNA synthesis, and, most impressively, a complete suppression of IL-2 secretion were observed in PKCbeta antisense ODN-treated cells. The data indicate a highly specific function of PKCbeta for regulation of TCR-CD28 induced-signaling, IL-2 gene expression and secretion in Jurkat T cells.
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PMID:Protein kinase Cbeta1, a major regulator of TCR-CD28-activated signal transduction leading to IL-2 gene transcription and secretion. 1291 61

4-1BB, a T cell co-stimulatory receptor, prolongs the survival and multiplication of CD4 T cells. Cross-linking 4-1BB stimulated expression of the anti-apoptotic genes bcl-XL and bcl-2, as well as of cyclins D2 and E, and inhibited expression of the cyclin-dependent kinase (cdk) inhibitor p27kip1. Ova-activated CD4 T cells of 4-1BB-deficient/DO11.10 TCR transgenic mice survived less well and underwent less expansion than cells of wild type DO11.10 TCR transgenic mice. These findings demonstrate that 4-1BB is a co-stimulatory molecule for CD4 T cell survival and expansion in vivo.
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PMID:4-1BB cross-linking enhances the survival and cell cycle progression of CD4 T lymphocytes. 1452 12

Numerous cell-to-cell signals tightly regulate CTL function. Human fibroblasts infected with HSV type 1 or 2 can generate such a signal and inactivate human CTL. Inactivated CTL lose their ability to release cytotoxic granules and synthesize cytokines when triggered through the TCR. Inactivation requires cell-to-cell contact between CTL and HSV-infected cells. However, inactivated CTL are not infected with HSV. The inactivation of CTL is sustainable, as CTL function remains impaired when the CTL are removed from the HSV-infected cells. IL-2 treatment does not alter inactivation, and the inactivated phenotype is not transferable between CTL, distinguishing this phenotype from traditional anergy and T regulatory cell models. CTL inactivated by HSV-infected cells are not apoptotic, and the inactivated state can be overcome by phorbol ester stimulation, suggesting that inactivated CTL are viable and that the signaling block is specific to the TCR. HSV-infected cells require the expression of U(S)3, a viral protein kinase, to transmit the inactivating signal. Elucidation of the molecular nature of this signaling pathway may allow targeted manipulation of CTL function.
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PMID:CTL are inactivated by herpes simplex virus-infected cells expressing a viral protein kinase. 1466 77

T lymphocyte activation is controlled by a coordinated web of tyrosine and serine kinases. There is a large body of information about tyrosine kinase substrates in T cells but analysis of serine kinase substrates has been more difficult. Recently we described an antiserum that recognizes serine-phosphorylated peptides corresponding to the substrate sequences for AGC serine kinases. This antiserum, termed PAP-1 (phospho antibody for proteomics-1), has proven useful for probing the serine phosphoproteome of antigen receptor-activated T lymphocytes. The present study shows that PAP-1 can also be used to explore serine kinases activated by cytokines and chemokines in T cells. Using PAP-1, together with proteomic analysis, the precursor form of the cytokine IL-16 (ProIL-16) was shown to be phosphorylated on Ser144 in antigen receptor-, SDF1alpha- and IL-2-activated T cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of ProIL-16 is dependent on activation of the kinases Erk1/2. IL-16 is secreted by mitogen-activated T cells, and the biochemical link between ProIL-16 and Erk1/2, revealed by studies with PAP-1, prompted analysis of the role of MAP kinases in this response. We show that TCR-mediated secretion of IL-16 is dependent on MAP kinases. The present study thus reveals how phosphoproteomic analysis opens previously unrecognized avenues for research, and yields novel insights about targets for MAP kinases in T lymphocytes.
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PMID:Identification of pro-interleukin 16 as a novel target of MAP kinases in activated T lymphocytes. 1476 64

Stimulation of T cells by peptide-presenting antigen-presenting cells (APCs) induces formation of a highly organized complex of receptors, signaling molecules and cytoskeleton components at the immune synapse (IS), the contact site between T cells and APCs. Conjugate formation between T cells and APCs initiates the formation of the IS. After this event, micrometer-scale molecular movements occur in the T cell plasma membrane and the actin cytoskeleton undergoes reorganization. Our current knowledge suggests that formation of the IS is an essential step during T cell activation. This is probably related to the proper localization of certain proteins in specific compartments. One of these proteins is protein kinase Ctheta (PKCtheta), which is absolutely required for T cell activation. During the last years we have made great advances in understanding the function and targets of this kinase, and recent reviews have summarized these findings. In contrast, we do not know the exact mechanism that activates PKCtheta after TCR engagement and the role of PKCtheta activation in the formation of the IS. In this review I analyze the mechanism of the translocation of PKCtheta and discuss the function of PKCtheta in the formation of the IS and, vice versa, the role of the IS in the translocation of PKCtheta.
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PMID:What came first: PKCtheta or the immune synapse? 1505 28

Cellular FLIP long form (c-FLIP(L)) is a caspase-defective homologue of caspase-8 that blocks apoptosis by death receptors. The expression of c-FLIP(L) in T cells can also augment extracellular signal-regulated kinase phosphorylation after TCR ligation via the association of c-FLIP(L) with Raf-1. This contributes to the hyperproliferative capacity of T cells from c-FLIP(L)-transgenic mice. In this study we show that activated CD4(+) T cells from c-FLIP(L)-transgenic mice produce increased amounts of Th2 cytokines and decreased amounts of Th1 cytokines. This correlates with increased serum concentrations of the Th2-dependent IgG1 and IgE. The Th2 bias of c-FLIP(L)-transgenic CD4(+) T cells parallels impaired NF-kappa B activity and increased levels of GATA-3, which contribute, respectively, to decreased IFN-gamma and increased Th2 cytokines. The Th2 bias of c-FLIP(L)-transgenic mice extends to an enhanced sensitivity to OVA-induced asthma. Taken together, these results show that c-FLIP(L) can influence cytokine gene expression to promote Th2-driven allergic reaction, in addition to its traditional role of blocking caspase activation induced by death receptors.
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PMID:Cellular FLIP long form-transgenic mice manifest a Th2 cytokine bias and enhanced allergic airway inflammation. 1506 48

The signal transduction of the cAMP/cAMP-dependent protein kinase [protein kinase A (PKA)] pathway through multiple receptors is critical for many processes in all cell types. In T cells, the engagement of both the TCR-CD3 complex and the CD28 co-stimulatory molecule also induces cAMP, and subsequently activates PKA. It is believed that elevation of cAMP levels in T cells is inhibitory of IL-2 production and T cell proliferation. However, the function and detailed signal transduction mechanisms of the cAMP/PKA pathway in naive T(h) cells are less well understood. In this study, we show that calcitonin gene-related peptide (CGRP) down-regulates IL-2 and IFN-gamma production and up-regulates IL-4 production to promote T(h)2 differentiation by moderate activation of the cAMP/PKA pathway via the CGRP receptor in the presence of a CD3/CD28 co-stimulation signal. The IL-4 production and transcriptional activation of T(h)2 cytokine mRNAs were also reproduced by the addition of a cAMP analogue, dibutyryl-cAMP, in CD3/CD28-stimulated naive T(h) cells. More interestingly, cAMP/PKA activation in naive T(h) cells stimulated with anti-CD3 plus anti-CD28 mAb is essential for inducing IL-4 production and promoting T(h)2 differentiation; in addition, NF-AT is a downstream effector of the cAMP/PKA signaling pathway. These findings indicate that the cAMP/PKA pathway transduces the critical activation signal to T(h)2 polarization by a CD3/CD28 co-stimulation signal and a PKA activating reagent.
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PMID:Up-regulation of IL-4 production by the activated cAMP/cAMP-dependent protein kinase (protein kinase A) pathway in CD3/CD28-stimulated naive T cells. 1509 85

Full transcriptional activity of the nuclear, DNA-bound form of NF-kappaB requires additional posttranslational modifications. In this study, we systematically mapped the T cell costimulation-induced phosphorylation sites within the C-terminal half of the strongly trans-activating NF-kappaB p65 subunit and identified serine 536 as the main phosphorylation site. The transient kinetics of serine 536 phosphorylation paralleled the kinetics of IkappaBalpha and IkappaB kinase (IKK) phosphorylation and also mirrored the principle of T cell costimulation. The TCR-induced pathway leading to serine 536 phosphorylation is regulated by the kinases Cot (Tpl2), receptor interacting protein, protein kinase Ctheta, and NF-kappaB-inducing kinase, but is independent from the phosphatidylinositol 3-kinase/Akt signaling pathway. Loss-of-function and gain-of-function experiments showed phosphorylation of p65 serine 536 by IKKbeta, but not by IKKalpha. Phosphorylation occurs within the cytoplasmic and intact NF-kappaB/IkappaBalpha complex and requires prior phosphorylation of IkappaBalpha at serines 32 and 36. Reconstitution of p65(-/-) cells either with wild-type p65 or a p65 mutant containing a serine to alanine mutation revealed the importance of this phosphorylation site for cytosolic IkappaBalpha localization and the kinetics of p65 nuclear import.
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PMID:Transient and selective NF-kappa B p65 serine 536 phosphorylation induced by T cell costimulation is mediated by I kappa B kinase beta and controls the kinetics of p65 nuclear import. 1512 24

The beta isoform of the type II regulatory subunit (RIIbeta) of protein kinase A suppresses CREB transcriptional activity and c-Fos production in T cells following activation via the TCR. Because CREB is an integral nuclear transcription factor for IL-2 production by T cells, we tested the hypothesis that RIIbeta down-regulates IL-2 expression and IL-2 production in T cells. Stable transfection of RIIbeta in Jurkat T cells led to an approximately 90% reduction in IL-2 mRNA and IL-2 protein following T cell activation. The inhibition of IL-2 production was associated with phosphorylation of the RIIbeta subunit at serine 114 (pRIIbeta) and localization of pRIIbeta in intranuclear clusters. A serine 114 phosphorylation-defective mutant, RIIbeta(S114A), did not form these intranuclear clusters as well as wild-type RIIbeta, and did not inhibit IL-2 mRNA and protein synthesis, indicating that serine 114 phosphorylation is required for both nuclear localization and down-regulation of IL-2 production by RIIbeta. In contrast to its effect on IL-2, RIIbeta induced constitutive up-regulation of CD154 mRNA and cell surface expression. Thus, pRIIbeta differentially regulates gene expression following T cell activation. Unexpectedly, we also found that stable overexpression of another protein kinase A regulatory subunit, RIalpha, had the opposite effect on IL-2 expression, causing a 3- to 4-fold increase in IL-2 production following stimulation. In summary, our data demonstrate a novel mechanism by which serine 114 phosphorylation and nuclear localization of RIIbeta controls the regulation of gene expression in T cells.
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PMID:Down-regulation of IL-2 production in T lymphocytes by phosphorylated protein kinase A-RIIbeta. 1518 64

The specific functions of p57(Kip2) in lymphocytes have not yet been fully elucidated. In this study, it is shown that p57(Kip2), which is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors, is present in the nuclei of normal resting (G(0)) T cells from peripheral blood and in the nuclei of the T cell-derived Jurkat cell line. Activation through the TCR results in rapid transport of cytoplasmic cyclin-dependent kinase 6 (cdk6) to nuclei, where it associates with cyclin D and p57(Kip2) in active enzyme complexes. Using purified recombinant proteins, it was shown in vitro that addition of p57(Kip2) protein to a mixture of cyclin D2 and cdk6 enhanced the association of the latter two proteins and resulted in phosphorylation of p57(Kip2). To probe further the function of p57(Kip2), Jurkat cells stably transfected with a plasmid encoding p57(Kip2) under control of an inducible (tetracycline) promoter were made. Induction of p57(Kip2) resulted in increased association of cdk6 with cyclin D3, without receptor-mediated T cell stimulation. The overall amounts of cdk6 and cyclin D3, and also of cdk4 and cyclin E, remained unchanged. Most notably, increased p57(Kip2) levels resulted in marked inhibition of both cyclin E- and cyclin A-associated cdk2 kinase activities and a decrease in cyclin A amounts. Therefore, although facilitating activation of cdk6, the ultimate outcome of p57(Kip2) induction was a decrease in DNA synthesis and cell proliferation. The results indicate that p57(Kip2) is involved in the regulation of several aspects of the T cell cycle.
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PMID:Identification of multiple cell cycle regulatory functions of p57Kip2 in human T lymphocytes. 1529 51


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