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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of membrane cofactor protein (MCP, CD46) on human T cell activation has been analyzed. Coligation of CD3 and CD46 in the presence of PMA or CD28 costimuli enhanced IL-2, IFN-gamma, or IL-10 secretion by CD4+ T lymphocytes. The effect of CD46 on IL-10 secretion did not require additional costimuli like anti-CD28 antibodies or phorbol esters. CD46 also enhanced IL-2 or IFN-gamma secretion by CD4+ blasts. In contrast, IL-5 secretion was inhibited upon CD46-CD3 coligation, in all the cells analyzed. These effects were independent of IL-12 and suggest that CD46 costimulation promotes a Th1-biased response in human CD4+ T lymphocytes. CD46 enhanced TCR/CD3-induced tyrosine phosphorylation of CD3zeta and ZAP-70, as well as the activation of the ERK, JNK, and p38, but did not modify intracellular calcium. The effect of specific inhibitors shows that enhanced ERK activation contributes to augmented IFN-gamma and lower IL-5 secretion and, consequently, to the Th1 bias. Cross-linking CD46 alone induced weak tyrosine phosphorylation of CD3zeta and ZAP-70. However, CD46 cross-linking by itself did not induce cell proliferation or lymphokine secretion, and pretreatment of CD4+ T lymphocytes with anti-CD46 antibodies did not significantly alter TCR/CD3 activation.
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PMID:CD46-mediated costimulation induces a Th1-biased response and enhances early TCR/CD3 signaling in human CD4+ T lymphocytes. 1530 76

Although IL-15 is known to be a T cell growth factor, the function in T cells of IL-15Ralpha, its high affinity receptor, remains unclear. We found that murine IL-15Ralpha(-/-) CD4(+) T cells hyperproliferated in response to TCR stimulation, in vitro and in vivo, and displayed a lower TCR activation threshold than wild-type CD4(+) T cells. TCR-induced activation of Zap70 and of the phospholipase C-gamma1-NFATp, Ras-ERK-c-Fos, and Rac-JNK-c-Jun pathways was all augmented in IL-15Ralpha(-/-) CD4(+) T cells. This in turn led to earlier IL-2Ralpha induction and higher IL-2 production, which most likely contribute to the hyperproliferation of IL-15Ralpha(-/-) CD4(+) T cells. Exogenous IL-15 reduced levels of TCR-activated signals, transcription factors, IL-2, and IL-2Ralpha, and division in wild-type CD4(+) T cells. These results reveal IL-15Ralpha to be a negative regulator for CD4(+) T cell activation and demonstrate a novel layer of regulation of TCR signaling by a cytokine system.
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PMID:IL-15Ralpha is a negative regulator of TCR-activated proliferation in CD4+ T cells. 1532 76

The assessment of cytokine production is an important component of studies of cell-mediated immune responses (CMI) to immunological challenges. In this study, we present a method to enhance the detection of cytokine-producing cells by allowing antigen-specific cells to expand in long-term culture. We investigated the influence of the degree of dilution of whole blood and the duration of the incubation period on whole blood as well as peripheral blood mononuclear cells (PBMCs), cultured in the absence or presence of mitogens, superantigens or specific antigens, for intracellular cytokine production (IFNgamma, TNFalpha, IL-2, IL-4, IL-10 and IL-13) by CD4+ and CD8+ T lymphocytes using four-colour flow cytometry. Whole blood was diluted 1/1, 1/2, 1/5 and 1/10, and cultured for 6, 24, 48, 72 and 120 h in the presence of antibodies against the co-stimulatory molecules CD28 and CD49d, and, during the last 4 h of culture, in the presence of brefeldin A. Optimum conditions for detection of a high number of IFNgamma-positive cells were observed after 72 h of culture in blood diluted 1/10. Median frequencies of IFNgamma+ cells obtained after activation by PMA-ionomycin, PHA or SEA-B were 29.3%, 20.0% and 6.8% for CD4+ cells, and 67.8%, 20.6% and 6.8% for CD8+ cells. In blood samples diluted 1/5 or 1/10, and cultured in the presence of cytomegalovirus (CMV) or varicella-zoster virus (VZV), mean peak levels of 2.8% and 1.4% IFNgamma+CD4+ cells were recorded at 120 h. The levels of cells producing cytokines other than IFNgamma were generally much lower and, in the case of IL-4 and IL-13, difficult to distinguish from background levels recorded in cultures with medium only. Kinetic studies of cytokine production by PBMCs showed a pattern similar to that of whole blood with peak levels of IFNgamma-producing cells recorded at 72 h. The increased levels of IFNgamma production after culture for 72 h were due to an expansion of the numbers of cytokine-producing cells responsive to a specific stimulus. Antigen-specific cells are usually present only at low levels in peripheral blood and may not be detected following simple activation for a few hours. To reach a level of detection in such cases, culture of diluted blood for several days is recommended.
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PMID:Optimum culture conditions for specific and nonspecific activation of whole blood and PBMC for intracellular cytokine assessment by flow cytometry. 1535 May 7

IL-2 stimulation of T lymphocytes induces the tyrosine phosphorylation and adaptor function of the insulin receptor substrate/Grb2-associated binder (Gab) family member, Gab2. In addition, Gab2 undergoes a marked decrease in its mobility in SDS-PAGE, characteristic of migration shifts induced by serine/threonine phosphorylations in many proteins. This migration shift was strongly diminished by treating cells with the MEK inhibitor U0126, indicating a possible role for ERK in Gab2 phosphorylation. Indeed, ERK phosphorylated Gab2 on a consensus phosphorylation site at serine 623, a residue located between tyrosine 614 and tyrosine 643 that are responsible for Gab2/Src homology 2 domain-containing tyrosine phosphatase (SHP)-2 interaction. We report that pretreatment of Kit 225 cells with U0126 increased Gab2/SHP-2 association and tyrosine phosphorylation of SHP-2 in response to IL-2, suggesting that ERK phosphorylation of serine 623 regulates the interaction between Gab2 and SHP-2, and consequently the activity of SHP-2. This hypothesis was confirmed by biochemical analysis of cells expressing Gab2 WT, Gab2 serine 623A or Gab2 tyrosine 614F, a mutant that cannot interact with SHP-2 in response to IL-2. Activation of the ERK pathway was indeed blocked by Gab2 tyrosine 614F and slightly increased by Gab2 serine 623A. In contrast, STAT5 activation was strongly enhanced by Gab2 tyrosine 614F, slightly reduced by Gab2 WT and strongly inhibited by Gab2 serine 623A. Analysis of the rate of proliferation of cells expressing these mutants of Gab2 demonstrated that tyrosine 614F mutation enhanced proliferation whereas serine 623A diminished it. These results demonstrate that ERK-mediated phosphorylation of Gab2 serine 623 is involved in fine tuning the proliferative response of T lymphocytes to IL-2.
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PMID:Phosphorylation of Grb2-associated binder 2 on serine 623 by ERK MAPK regulates its association with the phosphatase SHP-2 and decreases STAT5 activation. 1535 45

Mushroom polysaccharides are increasingly being utilized to treat a wide variety of diseases. Phellinus linteus proteoglycan (PL) has been reported to have anti-tumor and immunomodulatory properties. However, the cellular and molecular mechanism underlying its therapeutic effect is poorly understood. In this study, we investigated whether PL induces the phenotypic and functional maturation of murine bone marrow-derived dendritic cells (DC) and the possibility that Toll-like receptors (TLRs), which are known to be involved in immune-related responses, may be the receptor(s) of PL. The expression of surface molecules, including major histocompatibility complex (MHC) class II and CD86, increased on DC that were stimulated in a dose-dependent manner with PL, in comparison with unstimulated DC. Furthermore, PL increases the production of IL-12 by DC, as well as the IL-2 secretion and proliferation of allogeneic T cells. In addition, the activities of PL on DC were significantly reduced by treating the cells with anti-TLR2 or anti-TLR4 antibody (Ab) prior to PL, suggesting that both of them are possible receptors of PL. Also, maturation of DC by PL was able to directly activate mitogen-activated protein kinases (MAPKs), such as ERK1/2 and p38, and the nuclear transcription factor NF-kappaB p65. Also, the pretreatment of DC with inhibitors of NF-kappaB p65, and ERK and p38 MAPK signal pathways inhibited PL-induced up-regulation of surface molecules, such as MHC class II and CD86, and IL-12 production. Our results demonstrated that PL stimulation could induce the phenotypic and functional maturation of DC via TLR2 and/or TLR4 mediated-NF-kappaB, ERK and p38 MAPK signal pathways.
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PMID:Proteoglycan isolated from Phellinus linteus induces toll-like receptors 2- and 4-mediated maturation of murine dendritic cells via activation of ERK, p38, and NF-kappaB. 1546 14

Antioxidants can inhibit the proliferation of T lymphocytes induced by mitogens. This has been postulated to be due to their scavenging of reactive oxygen species which may act as second messengers in the antigen-induced signaling cascade leading to cell proliferation. When added concurrently with various mitogens, the thiol pyrrolidine dithiocarbamate (PDTC) inhibited the subsequent proliferation of lymphocytes. The extracellular copper chelator bathocuproine disulfonic acid (BCPS) increased the amount of PDTC needed for inhibition. We sought to determine the mechanism by which the two different treatments, PDTC (0.4 microM, copper-dependent) and PDTC (20 microM with BCPS, redox-sensitive) affected proliferation. We found that both inhibited the increase in expression of many of the genes, including IL-2 and MKP-2, that were induced early after stimulation of lymphocytes with phorbol myristate acetate and ionomycin. The inhibition of MKP-2 may have contributed to the enhancement observed by the thiol of mitogen-induced ERK phosphorylation. Of the two redox-sensitive, IL-2 regulating transcription factors, NF-kappaB and AP-1, the mitogen-induced activity of the former was inhibited by PDTC. Treatment of unstimulated cells with PDTC induced the expression of many genes, most notably several metallothioneins and heat shock proteins, and this may provide an alternative explanation for the inhibition of cellular proliferation.
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PMID:Effects of a redox-active agent on lymphocyte activation and early gene expression patterns. 1547 7

The turnover of phosphoinositides leading to PKC activation constitutes one of the principal axes of intracellular signaling. In T lymphocytes, the enhanced and prolonged PKC activation resulting from the engagement of the TcR and co-receptor molecules ensures a productive T cell response. The CD43 co-receptor promotes activation and proliferation, by inducing IL-2 secretion and CD69 expression. CD43 engagement has been shown to promote phosphoinositide turnover and DAG production. Moreover, PKC activation was found to be required for the activation of the MAP kinase pathway in response to CD43 ligation. Here we show that CD43 engagement led to the membrane translocation and enzymatic activity of specific PKC isoenzymes: cPKC (alpha/beta), nPKC (epsilon and theta;), aPKC (zeta) and PKCmu. We also show that activation of PKCtheta; resulting from CD43 ligation induced CD69 expression through an ERK-dependent pathway leading to AP-1, NF-kappaB activation and an ERK independent pathway promoting NFAT activation. Together, these data suggest that PKCtheta; plays a critical role in the co-stimulatory functions of CD43 in human T cells.
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PMID:PKCtheta is required for the activation of human T lymphocytes induced by CD43 engagement. 1552 11

The Jurkat T-cell line was used to study potential impact of deoxynivalenol (DON) and related 8-ketotrichothecenes on human immune function. DON (250-1000 ng/ml) readily induced caspase-3 and apoptosis in Jurkat cells. DON (62.5-500 ng/ml) also significantly upregulated IL-2 and IL-8 production following prestimulation with phorbol myristate acetate and ionomycin. DON markedly induced phosphorylation of p38, JNK 1/2, and ERK2. SB203580, a specific inhibitor of p38, reduced DON-induced apoptosis. The MEK1 inhibitor PD98059 which blocks ERK activation had only a small inhibitory effect on DON-induced apoptosis while the JNK inhibitor SP600125 was without effect. Inhibition of p38 attenuated DON-induced upregulation of IL-2 while all three MAPK inhibitors suppressed IL-8 upregulation. When effects of DON were compared to other 8-ketotrichothecenes, the concentrations of DON, 3-acetyl deoxynivalenol (3-ADON), 15-acetyl deoxynivalenol (15-ADON), nivalenol (NIV) and fusarenon X (FX) causing 50% apoptosis were 0.6, 0.5, 0.5, 0.5 and 7.5 microg/ml, respectively. Relative to IL-2 upregulation, FX was suppressive whereas 3-ADON, 15-ADON and NIV had no effect at concentrations of 62.5-500 ng/ml. In contrast, 15-ADON at 62.5-500 ng/ml and 3-ADON at 625-5000 ng/ml upregulated IL-8 production but FX and NIV had no effect. Taken together, these data suggest that DON's effects on apoptosis and cytokine production were differentially regulated by MAPKs. Although DON shared its capacity to induce apoptosis and potentiate IL-8 production with other 8-ketotrichothecenes, it appeared to be unique in its capacity to upregulate IL-2.
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PMID:Induction of apoptosis and cytokine production in the Jurkat human T cells by deoxynivalenol: role of mitogen-activated protein kinases and comparison to other 8-ketotrichothecenes. 1558 14

CD45 is dynamically repositioned within lipid rafts and the immune synapse during T cell activation, although the molecular consequences of CD45 repositioning remain unclear. In this study we examine the role of CD45 membrane compartmentalization in regulating murine T cell activation. We find that raft-localized CD45 antagonizes IL-2 production by opposing processive TCR signals, whereas raft-excluded CD45 promotes ERK-dependent polarized synaptic lipid raft clustering and IL-2 production. We propose that these dual CD45 activities ensure that only robust TCR signals proceed, whereas signals meeting threshold requirements are potentiated. Our findings highlight membrane compartmentalization as a key regulator of CD45 function and elucidate a novel signal transduction pathway by which raft-excluded CD45 positively regulates T cell activation.
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PMID:CD45 signals outside of lipid rafts to promote ERK activation, synaptic raft clustering, and IL-2 production. 1566 7

Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) is a hematopoietic-specific mammalian STE20-like protein serine/threonine kinase, comprised of a STE20-like kinase domain in its N-terminus, four proline-rich motifs, a caspase cleavage site, and a distal C-terminal Citron homology domain. HPK1 is involved in many cellular signaling cascades that include MAPK signaling, antigen receptor signaling, apoptosis, growth factor signaling, and cytokine signaling. HPK1 binds many adaptor proteins including members of the Grb2 family, Nck family, Crk family, SLP-76 family, and actin-binding adaptors like HIP-55. HPK1 tyrosine phosphorylation and kinase activation depend on the presence of adaptor proteins. Adaptor proteins are required not only for linking HPK1 to cell surface receptors like the EGFR, but also for downstream gene transcription like NFAT, AP-1 and IL-2. The HPK1 association with Crk, CrkL, and HIP-55 mediate HPK1-dependent c-Jun N-terminal kinase (JNK) activation, while the association of HPK1 with SLP-76, Gads, CrkL, Grb2, and Grap affect T- and B-cell dependent gene transcription. Interestingly, HPK1 has been implicated in both increasing and decreasing NFAT, AP-1, and IL-2 gene transcription in T-cells where adaptor proteins play a key role. Lastly, HPK1 will phosphorylate Crk and CrkL, in vitro, which presents a novel possibility for the regulation of adaptor proteins and downstream signaling events.
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PMID:Functional interactions of HPK1 with adaptor proteins. 1577 Jun 51


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