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)

Aggregation of the high affinity receptor for IgE (Fc epsilon RI) on the surface of mast cells results in the rapid hydrolysis of membrane inositol phospholipids by phospholipase C (PLC). Although at least seven isoenzymes of PLC have been characterized in different mammalian cells, the isoenzyme involved in Fc epsilon RI-mediated signal transduction and the mechanism of its activation have not been demonstrated. We now report that PLC-gamma 1 is translocated to the membrane of mast cells after aggregation of Fc epsilon RI. Activation of rat basophilic leukemia cells, a rat mast cell line, with oligomeric IgE resulted in an increase in PLC activity in washed membrane preparations in a cell free assay containing exogenous [3H]phosphatidylinositol (PI). The increase in PLC activity has the same dose-response to oligomeric IgE as receptor mediated hydrolysis of inositol lipids (PI hydrolysis) in intact cells. Analysis by Western blot probed with anti-PLC-gamma 1 antibody revealed that there is a three- to fourfold increase in PLC-gamma 1 in membranes from activated cells. The increase in PLC activity is augmented a further 20% by the addition of orthovanadate to the incubation medium suggesting that a tyrosine phosphatase is involved in the down-regulation of this phenomenon. These findings demonstrate translocation of PLC-gamma 1 to the membrane following activation of a receptor which does not contain intrinsic tyrosine kinase activity. Activation of PLC-gamma 1 by this pathway may account for Fc epsilon RI-mediated PI hydrolysis.
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PMID:Phospholipase C-gamma 1 is translocated to the membrane of rat basophilic leukemia cells in response to aggregation of IgE receptors. 131 4

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

We demonstrate using primary mast cell cultures derived from wild-type and CD45-deficient mice that mast cell triggering through the high-affinity immunoglobulin E (IgE) receptor requires the cell surface tyrosine phosphatase CD45. Unlike wild-type cells, cross-linking of surface-bound IgE in mast cells deficient in CD45 does not induce degranulation. Degranulation in these mutant cells does occur after treatment with the calcium ionophore A23187 indicating that the degranulation machinery is intact in these cells. We also demonstrate that the tyrosine phosphatase inhibitors orthoVanadate and perVanadate inhibit degranulation in wild-type mast cells, as does cross-linking of CD45 by anti-CD45 antibodies. Finally, we show that CD45-deficient mice are resistant to IgE-dependent systemic anaphylaxis. These results show that, like the T cell receptor and the antigen receptor on B cells, there is an absolute requirement for CD45 in signaling via the high affinity IgE receptor, expanding the number of receptors for which CD45 is an essential component.
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PMID:Leukocyte common antigen (CD45) is required for immunoglobulin E-mediated degranulation of mast cells. 804 27

Inhibitory receptors on hemopoietic cells critically regulate cellular function. Despite their expression on a variety of cell types, these inhibitory receptors signal through a common mechanism involving tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM), which engages Src homology 2 (SH2) domain-containing cytoplasmic tyrosine or inositol phosphatases. In this study, we have investigated the proximal signal-transduction pathway of an ITIM-bearing receptor, gp49B, a member of a newly described family of murine NK and mast cell receptors. We demonstrate that the tyrosine residues within the ITIMs are phosphorylated and serve for the association and activation of the cytoplasmic tyrosine phosphatase SHP-1. Furthermore, we demonstrate a physiologic association between gp49B and SHP-1 by coimmunoprecipitation studies from NK cells. To address the mechanism of binding between gp49B and SHP-1, binding studies involving glutathione S-transferase SHP-1 mutants were performed. Utilizing the tandem SH2 domains of SHP-1, we show that either SH2 domain can interact with phosphorylated gp49B. Full-length SHP-1, with an inactivated amino SH2 domain, also retained gp49B binding. However, binding to gp49B was disrupted by inactivation of the carboxyl SH2 domain of full-length SHP-1, suggesting that in the presence of the phosphatase domain, the carboxyl SH2 domain is required for the recruitment of phosphorylated gp49B. Thus, gp49B signaling involves SHP-1, and this association is dependent on tyrosine phosphorylation of the gp49B ITIMs, and an intact SHP-1 carboxyl SH2 domain.
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PMID:Specificity of the SH2 domains of SHP-1 in the interaction with the immunoreceptor tyrosine-based inhibitory motif-bearing receptor gp49B. 997 85

Interferon-gamma (IFN-gamma) is an important regulatory cytokine in cell proliferation, differentiation, adhesion, mediator release, and gene induction. This diversity of effector roles is achieved by a variety of incompletely understood mechanisms. In the mast cell (MC), IFN-gamma downregulates mediator synthesis and secretion. The present study demonstrates and characterizes for the first time IFN-gamma inhibition of adhesion of the MC analogue RBL-2H3 to the extracellular matrix protein fibronectin (FN). Inhibition requires preincubation of the cells with IFN-gamma for 20 hr, and is statistically significant at 100 U/ml IFN-gamma. Flow cytometry indicates that cell surface expression of very late antigen-4 (VLA-4), VLA-5, and the vitronectin receptor (VNR) remain constant following IFN-gamma treatment, indicating the inhibitory effect of IFN-gamma on adhesion to FN is not achieved through a reduction in integrin receptors for FN. Fluorescent labelling with Texas red phalloidin demonstrated rearrangement of the actin cytoskeleton in response to IFN-gamma was not significant. The tyrosine phosphatase inhibitor vanadate, and the nitric oxide (NO) synthase inhibitor L-NAME, reduced the IFN-gamma effect on adhesion to FN by 62 and 70%, respectively, demonstrating that the IFN-gamma effect is dependent upon the production of NO, potentially though a tyrosine phosphatase dependent mechanism. The NO donors sodium nitroprusside and S-nitrosoglutathione mimicked the effect of IFN-gamma. Thus, following stimulation with IFN-gamma, NO plays an autocrine role in the MC, and is able to modulate integrin function. This adds to the pathways NO is able to inhibit in the mast cell, shows that endogenous NO is able to inhibit these pathways, and suggests NO is impinging upon an element common to many signalling mechanisms in the MC.
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PMID:Interferon-gamma regulates the interaction of RBL-2H3 cells with fibronectin through production of nitric oxide. 1044 71

The transmembrane tyrosine phosphatase CD45 regulates the activity of src family protein tyrosine kinases (PTK) and thereby influences the signaling via such receptors as T and B cell antigen receptors associated with these PTK. However, its implication in signaling through the mast cell receptor with high affinity for IgE (FcepsilonRI) is less clear, although Lyn, a member of the src family, plays an important role in FcepsilonRI-mediated signaling. To define a role for CD45 in FcepsilonRI signal transduction, we established CD45 high expressing rat basophilic leukemia cell lines (RBL-CD45H) and cell lines expressing trace amounts of CD45 (RBL-CD45L). We demonstrate that although all RBL-CD45L cell lines degranulate following IgE- and antigen-induced FcepsilonRI aggregation, the response is significantly reduced at a low dose of antigen. The cells show a delayed and slowed Ca(2+) mobilization even though at a higher dose where the cells degranulate to a similar extent as RBL-CD45H. This diminished Ca(2+) response is restored by reconstitution of RBL-CD45L with a chimeric molecule containing the cytoplasmic phosphatase domains of rat CD45. Furthermore, tyrosine phosphorylation of FcepsilonRI, association of FcepsilonRI with Lyn and PTK activity associated with FcepsilonRI, all of which are enhanced upon FcepsilonRI aggregation in RBL-CD45H, are impaired in RBL-CD45L. Finally, we show that FcepsilonRI is physically associated with CD45 in RBL-CD45H prior to receptor aggregation. Thus, we propose that, although not indispensable in mast cell degranulation, CD45 positively regulates the signaling through FcepsilonRI by promoting the activation of FcepsilonRI-associated Lyn.
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PMID:Regulation of mast cell signaling through high-affinity IgE receptor by CD45 protein tyrosine phosphatase. 1065 52

In the present study, the effect of ceramide on antigen-stimulated phosphorylation of extracellular signal-regulated kinase (ERK) in the mechanism responsible for regulating production of prostaglandin (PG) D(2) was investigated in the mast cell line, RBL-2H3 cells. Cell-permeable C(6)-ceramide (N-hexanoylsphingosine) suppressed antigen-stimulated phosphorylation of ERK1/2 and p38 mitogen-activated protein kinase. Ceramide also inhibited production of PGD(2) and an increase in the activity of cytosolic phospholipase A(2) (cPLA(2)), whereas it did not influence the tyrosine phosphorylation of major cellular proteins in response to antigen. The ceramide-induced inhibition of ERK1/2 phosphorylation and of cPLA(2) activation was suppressed by orthovanadate, a tyrosine phosphatase inhibitor, but not by okadaic acid, a serine/threonine phosphatase inhibitor. Addition of ceramide to the lysate prepared from antigen-stimulated cells reduced the phosphorylated ERK1/2, and orthovanadate effectively prevented the reduction. These results suggest that ceramide accelerates the dephosphorylation of phosphorylated ERK1/2 via activation of a protein tyrosine phosphatase, thus preventing activation of cPLA(2) and production of PGD(2).
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PMID:Ceramide accelerates dephosphorylation of extracellular signal-regulated kinase 1/2 to decrease prostaglandin D(2) production in RBL-2H3 cells. 1169 58

gp49B1 is a member of the immunoglobulin (Ig) superfamily expressed on the surface of mast cells, macrophages, and activated natural killer cells. gp49B1 inhibits FcepsilonRI-induced activation of mast cells in vitro by virtue of two immunoreceptor, tyrosine-based inhibitory motifs that recruit the SHP-1 tyrosine phosphatase to the plasma membrane. We created gp49B1 null mice by targeted gene disruption, and found that IgE-dependent mast cell activation is augmented in these animals. Moreover, the ensuing anaphylactic reactions and inflammation are enhanced in the absence of gp49B1. Thus, gp49B1 innately counter-regulates mast cell activation mediated by Ig generated through the adaptive immune response in vivo.
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PMID:Inhibition of anaphylactic inflammation by the gp49B1 receptor on mast cells. 1221 99

Activating (PIR-A) and inhibitory (PIR-B) isoforms of the paired immunoglobulin (Ig)-like receptor family have been evaluated for their modulating potential in mast cell responses to IgE antibody and mast/stem cell growth factor (SCF). Mast cells produce PIR-A and PIR-B, but PIR-B was found to be predominantly expressed on the cell surface, where it was constitutively tyrosine phosphorylated and associated with SHP-1 tyrosine phosphatase. Efficient coligation of PIR-B with FcepsilonRI inhibited IgE-induced mast cell activation and serotonin release. PIR-B and c-kit (or mast/SCF receptor) coligation also inhibited SCF-induced mast cell responses. The PIR-B inhibitory activity was unimpaired in SHP-1-deficient mast cells, perhaps because of non-SHP-1-binding tyrosine-based inhibitory motif in the cytoplasmic tail of PIR-B. This analysis suggests that PIR-B may serve to control mast cell activity.
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PMID:Mast cell regulation via paired immunoglobulin-like receptor PIR-B. 1240 57

Human type 1 diabetes mellitus (T1DM) arises through autoimmune destruction of pancreatic beta cells and is modeled in many respects by the lymphopenic and spontaneously diabetic BioBreeding (BB) DRlyp/lyp rat. Previously, preonset expression profiling of whole DRlyp/lyp pancreatic lymph nodes (PLN) revealed innate immune activity, specifically that of mast cells and eosinophils. Furthermore, we observed that pancreatic islets of DRlyp/lyp rats as well as those of diabetes-inducible BB DR(+/+) rats potentially recruit innate cells through eotaxin expression. Here we determine that lifelong eotaxin expression begins before 40 days of life and is localized specifically to beta cells. In this report, we find that PLN mast cells are more abundant in DRlyp/lyp compared with related BB DR(+/+) rats (2.1 +/- 0.9% vs 0.9 +/- 0.4% of total cells, p < 0.0001). DRlyp/lyp PLN mast cell gene expression profiling revealed an activated population and included significant overrepresentation of transcripts for mast cell protease 1, cationic trypsinogen, carboxypeptidase A, IL-5, and phospholipase Cgamma. In the DR(+/+) rat, which develops T1DM upon depletion of T regulator cells, mast cells displayed gene expression consistent with the negative regulation of degranulation, including significant overrepresentation of transcripts encoding tyrosine phosphatase SHP-1, lipid phosphatase SHIP, and E3 ubiquitin ligase c-Cbl. To recapitulate the negative mast cell regulation observed in the DR(+/+) rats, we treated DRlyp/lyp rats with the mast cell "stabilizer" cromolyn, which significantly (p < 0.05) delayed T1DM onset. These findings are consistent with a growing body of evidence in human and animal models, where a role for mast cells in the initiation and progression of autoimmune disease is emerging.
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PMID:Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the BioBreeding rat. 1708 46


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