Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-13 (IL-13) and interleukin-4 (IL-4) are related in structure and function and are thought to share a common receptor component. We have investigated the signal transduction pathways activated by these two growth factors, as well as insulin, in cell-lines and primary cells of lymphohemopoietic origin. All three factors induced the tyrosine phosphorylation of a protein of 170 kDa (p170), which coimmunoprecipitated with the p85 subunit of P13'-kinase, via high affinity interactions mediated by the SH2 domains of p85. Antibodies raised against the entire insulin-receptor substrate-1 (IRS-1) protein immunoprecipitated p170 much less efficiently than they did IRS-1 from 3T3 cells. However, antibodies directed against the conserved pleckstrin homology domain of IRS-1 immunoprecipitated both p170 and IRS-1 with similar efficiency, suggesting they share structural similarities in this region. In lymphohemopoietic cells, IL-13, IL-4, and insulin failed to induce increased tyrosine phosphorylation of Shc, or its association with grb2, modification of Sos1, or activation of erk-1 and erk-2 mitogen-activated protein kinases, suggesting that p170 mediates downstream pathways distinct from those mediated by IRS-1. Both IL-13 and IL-4 induced low levels of tyrosine phosphorylation of Tyk-2 and Jak-1. IL-4 also activated the Jak-3-kinase, but, despite other similarities, IL-13 did not. Insulin failed to activate any of the known members of the Janus family of kinases. In that Jak-3 is reported to associate with the IL-2 gamma c chain, these data suggest that the IL-13 receptor does not utilize this subunit. However, both IL-13 and IL-4 induced tyrosine phosphorylation of the IL-4-140 kDa receptor chain, suggesting that this is a component of both receptors in these cells and accounts for the similarities in signaling pathways shared by IL-13 and IL-4.
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PMID:Interleukin-13 signal transduction in lymphohemopoietic cells. Similarities and differences in signal transduction with interleukin-4 and insulin. 774 81

The activation of erk/mitogen-activated protein kinases and p21ras is strongly associated with progression through the cell cycle. Cell growth induced by the cytokine interleukin-4 (IL-4) effectively dissociates the activation of p44erk-1 and p42erk-2 mitogen-activated protein kinases and p21ras from cell proliferation. In two cell lines of T lymphocyte and myeloid origin that were dependent upon IL-4 for continuous growth, IL-4 failed to detectably activate or induce tyrosine phosphorylation of p44erk-1 and p42erk-2. The activation of p21ras was also not detectably affected by IL-4 treatment of these cells. Treatment of the same cells with other growth factors (colony-stimulating factor-1 and Steel factor) or phorbol esters induced the tyrosine phosphorylation and activation of p44erk-1 and p42erk-2 and stimulated p21ras activity. The presence of IL-4 neither diminished nor enhanced the activation of p44erk-1 and p42erk-2 by colony-stimulating factor-1, Steel factor, or 12-O-tetradecanoylphorbol-13-acetate. Furthermore, IL-4 also failed to activate p44erk-1, p42erk-2, and p21ras in normal T lymphocytes and mast cells derived from spleen and bone marrow, respectively. Significantly, these findings demonstrate that IL-4-induced cell growth may be dissociated from the activation of p44erk-1, p42erk-2, and p21ras, suggesting that their activation may not be an absolute requirement for growth factor-stimulated mitogenesis.
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PMID:Interleukin-4-dependent proliferation dissociates p44erk-1, p42erk-2, and p21ras activation from cell growth. 811 29

The mammalian mitogen-activated protein (MAP) kinase homologue p38 has been shown to be activated by pro-inflammatory cytokines as well as physical and chemical stresses. We now show that a variety of hemopoietic growth factors, including Steel locus factor, colony stimulating factor-1, granulocyte/macrophage-colony stimulating factor, and interleukin-3, activate p38 MAP kinase and the downstream kinase MAPKAP kinase-2. Furthermore, although these growth factors activate both p38 MAP kinase and Erk MAP kinases, we demonstrate using a specific inhibitor of p38 MAP kinase, SB 203580, that p38 MAP kinase activity was required for MAP kinase-activated protein kinase-2 activation. Conversely p38 MAP kinase was shown not to be required for in vivo activation of p90(rsk), known to be downstream of the Erk MAP kinases. Interleukin-4 was unique among the hemopoietic growth factors we examined in failing to induce activation of either p38 MAP kinase or MAP kinase-activated protein kinase-2. These findings demonstrate that the activation of p38 MAP kinase is involved not only in responses to stresses but also in signaling by growth factors that regulate the normal development and function of cells of the immune system.
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PMID:Hemopoietic growth factors with the exception of interleukin-4 activate the p38 mitogen-activated protein kinase pathway. 901 68

CD45 plays a critical regulatory role in receptor signaling through its protein tyrosine phosphatase and Janus kinase (JAK) phosphatase activities. To investigate whether CD45 also plays a regulatory role in Ig class switching in human B cells, we examined the effects of CD45 triggering on Ig class switching to IgE and its relationship with CD45 JAK phosphatase activity. Anti-CD45 triggering of CD45 significantly inhibited interleukin-4 + anti-CD40-induced switch recombination in a switch recombination vector assay in stably transfected Ramos 2G6 human B cells, as well as Ig epsilon germ-line transcription and Smu-Sepsilon switch recombination in primary human B cells. These negative regulatory effects on Ig class switching were concomitant with the ability of CD45 to dephosphorylate the induced phosphorylation of JAK1, JAK3, and signal transducer and activator of transcription 6, but not on stress-activated/mitogen-activated protein kinases. We also showed that phosphorylated JAK1 and JAK3 were directly dephosphorylated by recombinant CD45 in vitro. These results indicate that CD45 is able to function as JAK phosphatase in human B cells and that this activity is directly associated with the negative regulation of the class switch recombination to IgE. CD45 may be an appropriate target drug for modulating IgE in allergic diseases.
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PMID:CD45 controls interleukin-4-mediated IgE class switch recombination in human B cells through its function as a Janus kinase phosphatase. 1199 88

The in vitro effects of gamma interferon (IFN-gamma) on the mouse CD5(+) B1-cell line, TH2.52, a hybridoma between mouse B lymphoma and mouse splenic B cells that expresses a series of B1 markers, were investigated. A significant number of macrophage-like cells appeared in the cultures of TH2.52 cells exposed to IFN-gamma, these adhering to plastic dishes and exhibiting phagocytic activity. Positive for esterase staining, the macrophage-like cells returned to the original TH2.52 morphology upon removal of IFN-gamma. The change was prevented by treatment with SB202190, an inhibitor of p38 mitogen-activated protein (MAP) kinase and by transfection of a p38 MAP kinase dominant-negative mutant. Further, interleukin-4 (IL-4) inhibited IFN-gamma-induced phosphorylation of p38 MAP kinase and the appearance of macrophage-like cells. IFN-gamma and IL-4 exhibited contradictory actions on morphological change of CD5(+) B1 cells into macrophage-like cells. Differential regulation of CD5(+) B1 cells by IFN-gamma, a Th1 cytokine, and IL-4, a Th2 cytokine, may have clear immunological significance.
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PMID:Change of mouse CD5(+) B1 cells to a macrophage-like morphology induced by gamma interferon and inhibited by interleukin-4. 1241 46

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CD66a) is a member of the immunoglobulin (Ig) superfamily, previously characterized as an adhesion and signaling molecule in epithelial, endothelial, and hematopoietic cells. Here, we show that the CEACAM1 isoform expression pattern is different in nonactivated and activated primary mouse B lymphocytes and that CEACAM1 influences B cell receptor complex-mediated activation. A CEACAM1-specific monoclonal antibody strongly triggered proliferation of mouse B cells when combined with surface IgM cross-linking. However, anti-CEACAM1 was not mitogenic when added alone. The proliferation was more pronounced and lasted longer as compared with other activators of B cells, such as anti-IgM in the presence of interleukin-4 or lipopolysaccharide. A similar, costimulatory effect was exerted by CEACAM1-expressing fibroblasts, indicating that homophilic CEACAM1-CEACAM1 cell-mediated binding is the physiological stimulus for CEACAM1-triggered B cell signaling. The anti-CEACAM1/anti-IgM-activated cells aggregated in a lymphocyte function-associated antigen-1-dependent manner. Furthermore, cells that were activated by anti-CEACAM1/anti-IgM secreted Ig but did not go through Ig class-switching. Anti-CEACAM1 induced phosphorylation of c-Jun N-terminal kinase (stress-activated protein kinase) but did not activate the extracellular signal-regulated kinase or p38 mitogen-activated protein kinases.
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PMID:CEACAM1 is a potent regulator of B cell receptor complex-induced activation. 1283 51

MUC2 mucin is a secretory glycoprotein which is produced from the intestinal goblet cells and is a major component of the intestinal epithelial mucus. The biological function of MUC2 mucin is considered to be the protection of intestinal epithelial surface, whereas the regulatory mechanism of MUC2 mucin production in immune response is not completely understood. We have studied the effects of cytokines, IL-4, IL-13 and TNF-alpha, on the regulation of MUC2 mRNA in the human colonic cancer cell lines, LS174T and HT29. The quantitative reverse transcription-polymerase chain reaction showed that single addition of IL-4, IL-13 and TNF-alpha to cell culture induced about two-fold increase of MUC2 mRNA level in LS174T cells. Interleukin-4 and IL-13 activated phosphorylation of mitogen-activated protein kinase in LS174T cells. A specific inhibitor of mitogen-activated protein kinase pathway, U0126, totally inhibited the increase of MUC2 mRNA by IL-4 or IL-13 in those cells. Therefore, mitogen-activated protein activation of kinase is required for the increase of MUC2 mRNA by IL-4 or IL-13 in LS174T cells. In contrast to LS174T cells, only TNF-alpha increased MUC2 mRNA through a mitogen-activated protein kinase pathway in HT29 cells that express low levels of MUC2 mRNA. These findings sustain a novel phenomenon that MUC2 mRNA expression is differently controlled by IL-4, IL-13, or TNF-alpha in LS174T and HT29 cells, whereas the mitogen-activated protein kinase pathway plays a role in the MUC2 mRNA expression induced by those cytokines in both cell lines.
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PMID:mRNA of MUC2 is stimulated by IL-4, IL-13 or TNF-alpha through a mitogen-activated protein kinase pathway in human colon cancer cells. 1284 48

Dendritic cells (DCs) are potent antigen-presenting cells that play a pivotal role in the initiation of T cell-dependent immune responses. Immature DCs obtained from peripheral blood CD14+ monocytes by culture with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) differentiate into mature DCs upon stimulation with lipopolysaccharide (LPS). At least three families of mitogen-activated protein kinases (MAPKs), that is, extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK) and p38 MAPK, are involved in the DC maturation process. We report investigations of the role of JNK in the maturation of human monocyte-derived DCs. SP600125, a specific inhibitor of JNK, inhibited the LPS-induced up-regulation of CD80, CD83, CD86 and CD54, but augmented the up-regulation of HLA-DR. SP600125 slightly inhibited the down-regulation of FITC-dextran uptake during DC maturation. However, SP600125 did not affect the LPS induced up-regulation of allostimulatory capacity of DCs. SP600125 inhibited the release of IL-12 p70 and TNF-alpha from mature DCs. Although autologous T cells primed by the ovalbumin (OVA)-pulsed mature DCs produced IFN-gamma, but not IL-4, OVA-pulsed SP600125-treated mature DCs could initiate IL-4 production from autologous T cells. In contrast, a p38 MAPK inhibitor, SB203580, profoundly inhibited the phenotypic and functional maturation of DCs, while an ERK inhibitor, PD98059, had little or no effect. Taken together, the JNK signaling pathway appears to have a role that is distinct from the p38 MAPK and ERK cascades in the maturation process of DCs, and may be involved in the augmentation of Th2-prone T cell responses when it is suppressed.
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PMID:Role of c-Jun N-terminal kinase on lipopolysaccharide induced maturation of human monocyte-derived dendritic cells. 1547 28

Crry/p65 is a type I glycoprotein, which protects mouse T cells from complement attack. We have previously shown that complement receptor I-related protein Crry/p65 (Crry) ligation has a costimulatory effect on mouse CD4+ T cell activation. Here, we have examined the mechanisms responsible for Crry costimulation, addressing the question of whether Crry potentiates signal transduction starting at the T cell receptor (TCR)/CD3 complex or promotes distinct costimulatory signals. We show that Crry increases early TCR-dependent activation signals, including p56lck-, zeta-associated protein-70 (ZAP-70), Vav-1, Akt, and extracellular signal-regulated kinase (ERK) phosphorylation but also costimulation-dependent mitogen-activated protein kinases (MAPK), such as the stress-activated c-Jun N-terminal kinase (JNK). It is intriguing that Crry costimulus enhanced p38 MAPK activation in T helper cell type 1 (Th1) but not in Th2 cells. A fraction of Crry is found consistently in the detergent-insoluble membrane fraction of Th1 or Th2 cells or CD4+ lymphoblasts. Crry costimulation induced clustering of lipid rafts, increasing their content in Crry, CD3epsilon, and p59-60 forms of p56lck, and caused actin polymerization close to the site of activation in Th2 cells. Such events were inhibited by wortmannin, suggesting a role for phosphatidylinositol-3 kinase in these effects. The Crry cytoplasmic domain was required for JNK activation and interleukin-4 secretion but not for the presence of Crry in rafts or activation of p56lck, ZAP-70, Akt, Vav-1, or ERK. This suggests that Crry costimulation involves two different but not mutually exclusive signal transduction modules. The dual function of Crry as a complement regulatory protein and as a T cell costimulator illustrates the importance of complement regulatory proteins as links between innate and adaptive immunity.
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PMID:Complement regulatory protein Crry/p65-mediated signaling in T lymphocytes: role of its cytoplasmic domain and partitioning into lipid rafts. 1630 24

The antiallergic activity of Polygoni cuspidati radix (PR) and the mechanism of action by which it functions were investigated in this study. The extract of PR exhibited potent inhibitory activity in mast cells; its IC50 values were 62 +/- 2.1 microg/ml for RBL-2H3 mast cells and 46 +/- 3.2 microg/m for bone marrow-derived mast cells by antigen stimulation, and it also suppressed the expression of tumor necrosis factor-alpha and interleukin-4 in RBL-2H3 cells. According to the in vivo animal allergy model, it inhibited a local allergic reaction, passive cutaneous anaphylaxis, in a dose-dependent manner. With regard to its mechanism of action, PR inhibited the activating phosphorylation of Syk, a key signaling protein for the activation of mast cells. It also suppressed Akt and the mitogen-activated protein kinases ERK1/2, p38, and JNK, which are critical for the production of various inflammatory cytokines in mast cells. The results of the study indicate that the antiallergic activity of PR is mediated through the inhibition of histamine release and allergic cytokine production by the inhibition of Syk activating phosphorylation in mast cells.
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PMID:Polygoni cuspidati radix inhibits the activation of Syk kinase in mast cells for antiallergic activity. 1804 66


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