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: UNIPROT:P15088 (mast cell)
14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunohistology of the nasal mucosa was examined in 13 grass pollen-sensitive patients and in seven normal nonatopic control subjects before and during the pollen season. Cryostat sections (6 microns) of biopsy specimens from the inferior turbinate were immunostained with the alkaline-phosphatase antialkaline-phosphatase method and a panel of monoclonal antibodies. Mast cell subtypes were measured with a double sequential immunostaining method. Within the submucosa, seasonal increases in total (MBP+, p less than 0.01) and "activated" (EG2+, p less than 0.01) eosinophils were observed for the patients, which were significant when these counts were compared with counts for those of control subjects (MBP+ p less than 0.01; EG2+ p less than 0.001). Within the nasal epithelium, seasonal increases in total (p less than 0.05) and "activated" (p less than 0.02) eosinophils were also observed. Mast cell counts revealed seasonal increases in tryptase-only positive mast cell (MCT) (p less than 0.02) but not chymase plus tryptase-positive mast cells (MCTC) within the epithelium that were significant when counts were compared with those of control subjects (p less than 0.03). No significant changes were observed within the submucosa or epithelium for total leukocytes (CD45+ cells) or T-lymphocytes (CD3+, CD4+, CD8+, and CD 25+ cells) for either group. Similarly, no significant changes were observed for neutrophils (antielastase), macrophages (CD68+), nor HLA-DR+ cells. In the subjects with rhinitis, seasonal submucosal CD3+ counts correlated with MBP+ eosinophils (r = 0.56; p less than 0.05) and MCTS (r = 0.65; p less than 0.02). Similarly, seasonal epithelial EG2+ eosinophil counts correlated with MCTs (r = 0.56; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunohistology of the nasal mucosa in seasonal allergic rhinitis: increases in activated eosinophils and epithelial mast cells. 153 8

Equilibrium sedimentation experiments of the native acid phosphatase indicate a dimer-tetramer dissociating nonequilibrating system with a dimer Mr = 180,000 g/mol. The hydrolysis of nitrophenylphosphate was used to determine the sedimentation coefficient of the active species. The s20,w value for the species which degrades nitrophenylphosphate is 13.52 +/- 0.46 S in 1% sucrose and 13.72 +/- 0.11 S in 1.3 M sodium chloride, corresponding to the Svedberg value of the tetramer species. Several lines of evidence are presented which, together with previous data, indicate that the Schizosaccharomyces pombe nonspecific acid phosphatase is composed of 4 identical or nearly identical polypeptide chains: a, equilibrium sedimentation analysis of the enzyme in denaturing agents indicates the presence of homogeneous material having Mr = 90,800 g/mol; b, digestion with carboxypeptidase A releases 0.82 mol of tyrosine/monomer molecular weight. Concomitant phosphatase inactivation occurred during the splitting off of the tyrosyl terminal residue. Furthermore, a unique NH2-terminal residue (histidine) was determined.
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PMID:Molecular properties and active form of nonspecific acid phosphatase from Schizosaccharomyces pombe. 721 63

FK506 and cyclosporin A (CsA) are immunosuppressive agents that inhibit IL-2 production by activated T cells, but only CsA inhibits IgE activation-induced cytokine transcripts in mouse IL-3-dependent, bone marrow-derived mast cells (BMMC). We previously associated the resistance of BMMC to FK506 with a deficiency in the expression of FK506 binding protein (FKBP) 12, a molecule that forms a complex with FK506 capable of inhibiting calcineurin phosphatase activity in vitro. In this report, we establish that FKBP12 mediates FK506 inhibition of both calcineurin phosphatase activity and IgE activation-induced cytokine transcripts in a Kirsten murine sarcoma virus-immortalized mast cell line that is FKBP12 deficient. Overexpression of FKBP12 by transfection enhanced the ability of FK506 to inhibit calcineurin phosphatase activity (IC50 = 2 nM), compared with cells transfected with the expression vector alone (IC50 > 30 nM). The IC50 value for FK506 inhibition of IgE activation-induced transcripts for TNF-alpha decreased from 40 nM in vector control cells to 10 nM in FKBP12 transfectants. Similarly, the IC50 value for inhibition of IL-6 transcripts decreased from > 1000 nM in vector control cells to 35 nM in FKBP12 transfectants. In contrast, activation-elicited release of the secretory granule mediator beta-hexosaminidase was only partially inhibited by FK506 at 1000 nM, regardless of the levels of FKBP12 expressed by the cells. Thus, FKBP12 is the dominant cytosolic protein that mediates FK506 inhibition of TNF-alpha and IL-6 transcripts.
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PMID:The complex of FK506-binding protein 12 and FK506 inhibits calcineurin phosphatase activity and IgE activation-induced cytokine transcripts, but not exocytosis, in mouse mast cells. 753 Jul 43

The immunosuppressive drugs FK506 and rapamycin bind to a family of intracellular proteins termed FK506-binding proteins (FKBP). FK506 and rapamycin inhibit lymphocyte-activation pathways by forming complexes with an FKBP; subsequently, the drug/FKBP complexes interact with target molecules involved in signal transduction. A key target of FK506/FKBP12 complexes is calcineurin, a calcium- and calmodulin-dependent serine/threonine phosphatase. In mammalian cells, rapamycin treatment is associated with inhibition of the activity of several cellular serine/threonine kinases, including p70 S6 kinase. These kinases may function in signaling pathways involving TOR gene producs, which have been shown to interact with rapamycin/FKBP12 complexes in vitro. To determine if FKBP12 mediates the effects of both FK506 and rapamycin in mammalian cells, we overexpressed FKBP12 in a murine mast cell line. Increased expression of FKBP12 resulted in increased sensitivity to FK506 and rapamycin, as measured by inhibition of calcineurin activity and p70 S6 kinase activity, respectively. In contrast, overexpression of FKBP25 had no effect on sensitivity to either drug. Two distinct point mutations in FKBP12, one altering a hydrophobic residue within the drug-binding pocket and the other changing a charged surface residue of FKBP12, abrogated its ability to mediate sensitivity to FK506 and rapamycin. These results establish that FKBP12 can mediate sensitivity to both FK506 and rapamycin in mammalian cells.
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PMID:FK506 binding protein 12 mediates sensitivity to both FK506 and rapamycin in murine mast cells. 753 90

The cDNA encoding the rat equivalent of the human hematopoietic tyrosine phosphatase, also known as leukocyte phosphatase, was isolated from a rat basophilic leukemia mast cell cDNA library. By two-dimensional electrophoresis, the protein expressed in the mast cells was of a size (40 kDa) and pI (6.9) predicted from the deduced amino acid sequence. Thus, although previously shown to be preferentially expressed in T cells and B cells, the phosphatase is also found in mast cells. By immunofluorescence microscopy, rat hematopoietic tyrosine phosphatase localized to discrete, globular compartments within the cytoplasm and was not found either in the nucleus or associated with the cell surface membrane. Aggregation of high affinity IgE receptors in the mast cells induced tyrosine phosphorylation of the phosphatase. The tyrosine phosphorylation was mimicked by stimulation with calcium ionophore A23187 but not by direct activation of protein kinase C. Since phosphorylation of the phosphatase was dramatically reduced when the cells were activated in Ca(2+)-free media, it is dependent on a rise in intracellular Ca2+. These data strongly suggest that hematopoietic tyrosine phosphatase may be involved in the IgE receptor-mediated signaling cascade.
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PMID:Aggregation of IgE receptors in rat basophilic leukemia 2H3 cells induces tyrosine phosphorylation of the cytosolic protein-tyrosine phosphatase HePTP. 754 70

Protein tyrosine phosphorylation is an early event in the high affinity IgE receptor (Fc epsilon RI)-mediated signaling cascade leading to secretion in mast cells. Numerous proteins, including the beta- and gamma-subunits of Fc epsilon RI, become tyrosine phosphorylated after receptor aggregation. Dephosphorylation of these proteins may be important to reverse and limit transmembrane signaling. RBL-2H3 mast cell lysates were found to contain protein tyrosine phosphatase activity that dephosphorylated the tyrosine-phosphorylated beta- and gamma-subunits of Fc epsilon RI. The protein tyrosine phosphatase activity associated with Fc epsilon RI and was equally present with receptors from nonactivated and stimulated cells. Moreover, the phosphatase eluted from the immunoprecipitates and, when added back, dephosphorylated both tyrosine-phosphorylated beta- and gamma-subunits, but not tyrosine-phosphorylated Lyn or Syk. These results strongly suggest that the IgE receptor-associated protein tyrosine phosphatase may regulate the steady state level of tyrosylphosphate of the beta- and gamma-subunits and, therefore, may modulate the interaction of these subunits with other downstream molecules, such as Syk.
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PMID:Protein tyrosine phosphatase activity associates with the high affinity IgE receptor and dephosphorylates the receptor subunits, but not Lyn or Syk. 759 47

Nuclear factor of activated T-cells (NFAT) is a transcriptional activator that binds to the interleukin-2 promoter and is believed to be responsible for T-cell-specific interleukin-2 gene expression. Here we demonstrate using electrophoretic mobility shift assays that nuclear NFAT can be induced in the rat basophilic leukemia (RBL-2H3) mast cell line and rat bone marrow-derived mast cells upon cross-linkage of the high affinity receptor (Fc epsilon RI) for immunoglobulin E (IgE). Receptor-dependent activation of NFAT was mimicked by the combination of the protein kinase C activator phorbol myristate acetate and the calcium ionophore ionomycin. The induced binding activity was specific for the NFAT recognition motif because competition with nonradioactive NFAT oligonucleotide abolished the DNA binding activity, whereas nonradioactive oligonucleotides recognized by the transcription factors NF kappa B, glucocorticoid receptors, and TFIID did not. An oligonucleotide representing the AP-1 recognition sequence also blocked the NFAT DNA binding activity, as did a combination of anti-Fos and anti-Jun antibodies. Using electrophoretic mobility shift assays, AP-1-binding proteins were found to be induced in RBL-2H3 cells under the same conditions as was the NFAT binding activity. Together these data suggest that the NFAT complex in mast cells contains Fos and Jun proteins as does NFAT in T-cells. The appearance of nuclear NFAT binding activity was dependent in part upon calcium mobilization, as buffering the antigen-induced calcium rise with intracellular BAPTA strongly inhibited NFAT activation. Prevention of calcium influx with external EGTA also inhibited NFAT activation, indicating that release of calcium from internal stores was insufficient for sustained activation of mast cell NFAT. Cyclosporin A, a potent inhibitor of the calmodulin-dependent phosphatase calcineurin, blocked the induction of NFAT-DNA binding activity, implicating calcineurin as a key signaling enzyme in this pathway. These results suggest that NFAT is present in the mast cell line RBL-2H3 and in primary bone marrow-derived mast cells, is similar in subunit composition to the T-cell NFAT, and may play a role in calcium-dependent signal transduction in mast cells.
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PMID:Fc epsilon RI-mediated induction of nuclear factor of activated T-cells. 760 2

In the present study we examined the activation of Ca(2+)-sensitive cytosolic phospholipase A2 (cPLA2) after aggregation of cell-surface high-affinity Fc receptors for IgE (Fc epsilon RI) on mast cells. MCII mast cells (a factor-dependent bone-marrow-derived murine mast cell line) produce significant amounts of leukotriene C4 (LTC4) (70 ng/10(6) cells) on cross-linking of Fc epsilon RI. Using enzymic and immunochemical analysis we found that cPLA2 is the predominant form of this enzyme in MCII mast cells (0.2 micrograms/mg of total protein) and other forms (i.e. secretory PLA2 or Ca2+ independent cytosolic PLA2) could not be detected. Therefore MCII mast cells represent an excellent cellular model for the study of the biochemical mechanism(s) responsible for Fc epsilon RI-induced activation of cPLA2 and the involvement of cPLA2 in Fc epsilon RI-mediated production of LTC4. After activation of Fc epsilon RI by cross-linking, cPLA2 in MCII mast cells exhibited a decreased electrophoretic mobility and its enzyme activity was increased 3-fold. Treatment with phosphatase reversed both the altered electrophoretic mobility and the enhanced enzyme activity demonstrating that they were the result of Fc epsilon RI-induced phosphorylation. On cross-linking of Fc epsilon RI, cPLA2 was phosphorylated within 30 s and appeared to be an early substrate for Fc epsilon RI-activated protein kinases in MCII mast cells. Tyrosine phosphorylation may be a critical component in this process, as genistein, an inhibitor of protein tyrosine kinases, blocked the activation of cPLA2. Using anti-phosphotyrosine antibodies we observed that the activating phosphorylation was not on tyrosine residues of cPLA2, indicating that tyrosine kinases participate upstream in the signalling cascade that couples Fc epsilon RI to cPLA2. We conclude that in MCII mast cells cPLA2 is activated by kinase-dependent mechanisms and may be responsible for Fc epsilon RI-induced mobilization of arachidonic acid for the generation of LTC4.
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PMID:Phosphorylation and activation of Ca(2+)-sensitive cytosolic phospholipase A2 in MCII mast cells mediated by high-affinity Fc receptor for IgE. 781 99

We demonstrated previously that the low-affinity IgG receptors Fc gammaRIIB, which are coexpressed with the high-affinity IgE receptors Fc epsilonRI in mouse mast cells, can inhibit IgE-induced release of inflammatory mediators and cytokines by these cells. Inhibition was found to require the coaggregation of the two receptors and to depend on the presence of a tyrosine-based inhibition motif (ITIM) in the intracytoplasmic domain of Fc gammaRIIB. We report here that the coaggregation with Fc gammaRIIB does not prevent Fc epsilonRI from triggering activation signals in BMMC and induces the tyrosine phosphorylation of Fc gammaRIIB. Phosphorylated ITIM peptides bound in vitro to three SH2 domain-containing phosphatases present in BMMC lysates: the phosphotyrosine phosphatases SHP-1 and SHP-2. and the inositolphosphate phosphatase SHIP. Using BMMC generated from the SHP-1-deficient motheaten mice, SHP-1 was found to be dispensable for inhibition of mast cell activation. When analyzed for in vivo association, SHIP coprecipitated with phosphorylated Fc gammaRIIB, whereas SHP-1 or SHP-2 did not. These observations altogether indicate that Fc epsilonRI actively participates in its own regulation and that the mechanisms by which Fc gammaRIIB inhibit cell activation might be different in mast cells and in B-cells.
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PMID:Selective in vivo recruitment of the phosphatidylinositol phosphatase SHIP by phosphorylated Fc gammaRIIB during negative regulation of IgE-dependent mouse mast cell activation. 905 59

We analyzed the effect of rapamycin on autocrine mast cell tumor lines with abnormally stable interleukin-3 (IL-3) transcripts due to a defect in mRNA degradation. Rapamycin inhibited IL-3 mRNA expression specifically, while transcripts of IL-4 and IL-6 were not affected. As indicated by the use of the transcriptional inhibitor actinomycin D or by reporter constructs, inhibition was posttranscriptional and resulted from destabilization of the mRNA. Transcripts from transgenes lacking the AU-rich 3' untranslated region were refractory to drug-induced degradation, suggesting that these 3' sequences contain the target of the rapamycin effect. Rapamycin did not promote IL-3 mRNA degradation in cells of a tumor variant lacking expression of FKBP12, the binding protein of rapamycin. Experiments with wortmannin indicated that rapamycin does not act via p70S6 kinase. FK-506, another ligand of FKBP12 affecting the phosphatase calcineurin, did not antagonize but shared the effect of rapamycin. Our data fit a model whereby both FKBP12 and calcineurin target an unknown regulator of IL-3 mRNA turnover.
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PMID:Rapamycin destabilizes interleukin-3 mRNA in autocrine tumor cells by a mechanism requiring an intact 3' untranslated region. 915 24


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