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)

Ws/Ws rats have a small deletion at the tyrosine kinase domain of the c-kit gene and are deficient in both mucosal mast cells (MMC) and connective tissue-type mast cells (CTMC). The role of the c-kit receptor in the development of MMC and CTMC was investigated by infecting Ws/Ws and control +/+ rats with Nippostrongylus brasiliensis (NB), which induces T-cell-dependent mast cell proliferation. Although mast cells did not develop in the skin of Ws/Ws rats, a significant number of mast cells developed in the jejunum after NB infection. These mast cells had the MMC protease phenotype (rat mast cell protease [RMCP] I-/II+) and lacked heparin because they were not stained with berberine sulfate. Globule leukocytes were also detected in the mucosal epithelium of these rats. However, the number of MMC and the serum concentration of RMCP II in NB-infected Ws/Ws rats were only 13% and 7% of those of NB-infected +/+ rats, respectively. A small number of mast cells also developed in the lung, liver, and mesenteric lymph nodes of Ws/Ws rats after NB infection. Although mast cells in these tissues had the MMC phenotype throughout the observation period, the increased mast cells in the lung and liver of +/+ rats acquired a CTMC-like phenotype and were RMCP I+/II+, berberine sulfate+, and formalin resistant. These results indicate that the need for the stimulus through the c-kit receptor appears to be greater in the development of CTMC in the skin as well as for CTMC-like mast cells in the lung and liver than for the development of MMC.
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PMID:Infection of Nippostrongylus brasiliensis induces development of mucosal-type but not connective tissue-type mast cells in genetically mast cell-deficient Ws/Ws rats. 768 22

It is well established that mast cell proliferation and maturation are regulated by two principle cytokines, IL-3 and the c-kit ligand stem cell factor (SCF). Little is known, however, how these two processes are negatively regulated and thus, how mast cell number is controlled in normal or pathologic processes. In this study we hypothesized that IL-3-dependent mast cells would undergo programmed cell death (apoptosis) on removal of IL-3 as was shown with other growth factor-dependent hemopoietic cells. Apoptotic changes were analyzed using light microscopy, fluorescent staining with acridine orange, flow cytometric analysis, and DNA electrophoresis. We could demonstrate that elimination of IL-3 from either primary bone marrow-derived cultured mast cell cultures (BMCMC) or from the growth factor-dependent mast cell line MCP5 resulted in the characteristic changes of apoptosis including condensed chromatin, fragmented nuclei, cellular vacuolization, typical pattern of propidium iodide or Hoechst 33342 uptake by flow cytometry, and the characteristic 200 bp "ladder" pattern of DNA cleavage. These events were prevented by SCF, an action that was in part mediated by tyrosine kinases, in that the tyrosine kinase inhibitor herbimycin inhibited the action of SCF in preventing apoptosis in IL-3-deprived cells. By using anti c-kit mAb and IL-3-dependent BMCMC obtained from W/Wv mice homozygous for mutation at the w locus that encodes the c-kit receptor, we could also show that SCF exerted its effect via c-kit. Neither dexamethasone nor cyclosporin A inhibited the "rescue" effect of SCF, suggesting that "rescue" was mediated by SCF and not through the induction of other cytokines. Thus, IL-3-dependent mast cells undergo apoptosis on removal of IL-3, an event that is prevented by the addition of SCF through its ligand c-kit, thus demonstrating how these principle mast cell growth factors may act in concert to regulate mast cell number under physiologic conditions.
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PMID:IL-3-dependent murine mast cells undergo apoptosis on removal of IL-3. Prevention of apoptosis by c-kit ligand. 769 Aug 14

Protein-tyrosine phosphorylation plays a critical role in the high-affinity IgE receptor (Fc epsilon RI) signaling. Here we investigated the involvement of the tyrosine kinase p72syk in Fc epsilon RI signaling in the rat mast cell line RBL-2H3. Specific antibodies were raised against peptides synthesized on the basis of the deduced peptide sequence of an essentially full-length rat syk cDNA. The expression of p72syk in RBL-2H3 cells was demonstrated with these antibodies. The aggregation of Fc epsilon RI led to the tyrosine phosphorylation of p72syk that was detected after 15 s of stimulation, reached a plateau by 5 min, and was not induced by calcium influx or protein kinase C activation. Association of p72syk with the tyrosine phosphorylated Fc epsilon RI gamma chain was detected only after receptor aggregation. We previously demonstrated that aggregation of the Fc epsilon RI on mast cells results in the tyrosine phosphorylation of a 72-kDa protein (pp72) involved in IgE signaling. The depletion of p72syk from RBL-2H3 cell lysates resulted in only a slight decrease in the amount of pp72. These results demonstrate that pp72 is composed of several phosphoproteins and identify p72syk as one component of pp72. These data, together with recent observations in T cells, indicate that the interaction between p72syk-related tyrosine kinases and zeta-related proteins could play an important role in signal transduction.
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PMID:Protein-tyrosine kinase p72syk in high affinity IgE receptor signaling. Identification as a component of pp72 and association with the receptor gamma chain after receptor aggregation. 769 87

Our current model of the events that occur in the first few seconds after Fc epsilon RI cross-linking focuses primarily on the role of tyrosine phosphorylation and its ability to direct specific protein-protein interactions through SH2 domains. Contact of a mast cell bearing appropriately liganded Fc epsilon RI with multivalent antigen results in the approximation of receptors initially into chains. The proximity of receptors in these chains allows the phosphorylation of their ARAMs by the lyn tyrosine kinase. ARAM phosphorylation results in binding of syk specifically to cross-linked receptors and its probable subsequent phosphorylation and activation by lyn. Activated syk then phosphorylates and activates PLC gamma 1 and PLC gamma 2, resulting in their activation and translocation to the membrane. The presence of active PLC gamma 1 and PLC gamma 2 on the cell membrane results in hydrolysis of membrane phosphatidyl inositol and the production of 1,4,5 inositol triphosphate. Inositol 1,4,5 triphosphate diffuses to the sarcoplasmic reticulum and causes the release of sequestered calcium. This model represents a snapshot of the current body of knowledge about Fc epsilon RI-mediated signal transduction. Given the rapid pace of research in this field, it will likely be incorrect or incomplete in at least some respects by the time of publication. Ideally, the information presented here should provide a framework on which to build for those interested in learning more about Fc epsilon RI in particular and multisubunit antigen receptors in general.
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PMID:Initial events in Fc epsilon RI signal transduction. 779 51

A number of new observations have added to our understanding of mast cell biology and the relevance of this cell to the genesis of asthma. The purpose of this review has been to highlight this new information and to refer the reader to extensive reviews where previously documented and well-known data are available. Of particular current interest is the knowledge that mast cell growth and differentiation is regulated by a specific molecule, stem cell factor, which interacts with a receptor on the surface of the mast cell (a tyrosine kinase) and that mast cell phenotype may be modulated by exposure to stem cell factor as well as to a host of inflammatory cytokines. In addition to the ability to release vasoactive/spasmogenic mediators characterized by histamine, the slow-reacting substance of anaphylaxis (sulfidopeptide leukotrienes), platelet-activating factor, and adenosine, the mast cell can release a unique family of enzymes and generate a cassette of cytokines with critically important pro-inflammatory potential. The enzymes that are unique to the mast cell can potentiate a number of inflammatory events central to asthma, including fibroblast activation, mucus secretion, smooth muscle contraction, and neuropeptide degradation, while the cytokines may directly influence the influx, persistence, and activity of inflammatory cells, particularly eosinophilis and basophils, through the ability of the cytokines to modulate endothelial expression of leukocyte adhesion receptors and to prevent target cell apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mast cells and airway inflammation in asthma. 795 90

IgE molecules bind mast cells via a heterotetrameric receptor termed Fc epsilon RI. Cross-linking of bound IgE by specific allergen (Ag) initiates a signal transduction cascade resulting in a degranulation response. Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in isoprenoid and sterol biosynthesis, by the cholesterol-lowering drug, lovastatin, blocks Fc epsilon RI-dependent [3H] serotonin ([3H]5HT) release from the mast cell line, RBL-2H3. We studied the mode and locus of action of lovastatin in these cells. Lovastatin inhibited Ag-stimulated degranulation, as well as that evoked by ionomycin or by phorbol 12-myristate 13-acetate and ionomycin, stimuli which bypass early receptor events. Inhibition was concentration-dependent, occurred at levels which reduce lipid synthesis, and was reversible by addition of mevalonic acid, the product of the reductase reaction. The effects of lovastatin were not mimicked by treatment with the sterol demethylase inhibitor, econazole, suggesting that nonsterol isoprenoid synthesis is required for the degranulation response. Conversely, tyrosine kinase inhibitors from three disparate chemical classes reduced stimulus-evoked [3H]5HT release in a manner similar to lovastatin, suggesting that these agents share similar loci of action. Accordingly, lovastatin altered the phosphorylation pattern in unstimulated RBL-2H3, and reduced the phosphorylation response to IgE cross-linking. By analogy to 5HT release, this effect was concentration-dependent and mevalonic acid-reversible. The tyrosine kinase inhibitor, geldanamycin, also reduced the phosphorylation response to Ag. Lyn, a Src-related tyrosine kinase activated upon IgE cross-linking, was little influenced by either lovastatin or geldanamycin. Thus, lipid synthesis inhibition by lovastatin results in impaired tyrosine phosphorylation in RBL-2H3. This impairment is reflected in the subsequent exocytotic response. While lovastatin may inhibit tyrosine phosphorylation via an indirect mechanism, our results with tyrosine kinase inhibitors support the concept that multiple tyrosine kinases participate in the Fc epsilon RI-dependent signal transduction process.
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PMID:3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibition in a rat mast cell line. Impairment of tyrosine kinase-dependent signal transduction and the subsequent degranulation response. 832 96

The beta-type receptor of platelet-derived growth factor (beta PDGFR) is a class III transmembrane receptor with tyrosine kinase activity. The beta PDGFR gene is located on mouse chromosome 18 close to the c-fms gene which codes for the colony stimulating factor-1 receptor (CSF-1R). We previously reported that in a high percentage of myeloblastic leukemias induced by the Friend helper murine leukemia virus (F-MuLV), proviruses were integrated in the first intron of the c-fms gene leading to an enhanced expression of c-fms mRNA. Since activation by proviral insertion can act at long distance, we studied beta PDGF receptor gene expression in murine myeloblastic leukemias. This gene was found to be frequently expressed but the level of beta PDGF receptor mRNA was weak and not related to proviral activation. High affinity binding sites were expressed on myeloblastic cells and ligand binding induced cell proliferation. To determine whether beta PDGFR expression is a common feature in hematopoietic cells, we tested cell lines belonging to other hematopoietic lineages. We found that multipotent stem and mast cell lines also expressed the beta PDGF receptor gene. This suggests that PDGF, known as a mitogen for connective tissue cells, could also play a role in normal hematopoiesis.
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PMID:Expression of functional beta-platelet-derived growth factor receptors on hematopoietic cell lines. 848 8

As part of our studies aimed at exploring the potential role(s) of protein phosphatases in mast cell signaling, we analyzed the phosphorylation status of tyrosine-containing proteins in a rat mast (RBL) cell line that expresses both native rat high affinity IgE receptors (FcepsilonRI) and functional human FcepsilonRIalpha. After FcepsilonRI aggregation, there was a rapid increase in the tyrosine phosphorylation of a number of proteins, including those of m.w. 72 and 110 kDa. Concurrent with these events, however, there was a rapid dephosphorylation of a 100-kDa protein that was constitutively phosphorylated in the unstimulated cells. Using a specific mAb, this 100-kDa protein was identified as the GTPase dynamin. Dynamin was shown to associate with the SH3 domain of the src-related tyrosine kinase p56lyn in RBL 2H3 cells both in vitro and in vivo. FcepsilonRI aggregation causes rapid internalization of the aggregated receptors via clathrin-coated pits and dynamin is known to play a role in clathrin-mediated endocytosis, so the dephosphorylation of dynamin may provide the signal for targeting the aggregated receptors to the endocytic pathway.
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PMID:Rapid dephosphorylation of the GTPase dynamin after FcepsilonRI aggregation in a rat mast cell line. 875 30

Ag stimulation of mast cells via the IgE receptor (Fc epsilon RI) elicits production and release of numerous cytokines. This activation of Fc epsilon RI initiates various tyrosine kinase-dependent signaling cascades, which ultimately result in the de novo synthesis of cytokines. To date, no heterotrimeric G proteins have been implicated in this process. Here we report that the alpha subunit of the heterotrimeric G protein, Gz, can regulate production of the cytokine, TNF-alpha. The alpha subunit was overexpressed in a cultured mast cell line (RBL-2H3) known to contain G alpha z. In stimulated cells, overexpression of G alpha z significantly enhanced the production of TNF-alpha. This effect of G alpha z appeared to be restricted in that constitutive synthesis of the cytokine, TGF-beta, and Ag-stimulation of the phosphoinositide-dependent secretory pathway were not significantly affected. Thus, G alpha z, a heterotrimeric G protein, appeared to modulate the stimulatory pathways for induction of TNF-alpha synthesis in RBL-2H3 cells.
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PMID:Enhancement of TNF-alpha synthesis by overexpression of G alpha z in a mast cell line. 875 48

The c-kit gene is allelic with the dominant spotting (W) locus on mouse chromosome 5 and encodes a receptor tyrosine kinase. The ligand for c-kit receptor is stem cell factor (SCF), which is the principal growth factor for mast cells. The loss-of-function mutations of c-kit receptor affect the development of mast cells, thereby resulting in a depletion of mast cells. The abundant expression of c-kit receptor is indispensable for the survival of mast cells. In addition, the gain-of-function mutations of c-kit receptor were found in several tumor mast cell lines. When these gain-of-function mutations were introduced to cells of murine interleukin (IL)-3-dependent cell lines, the expression of c-kit receptor with constitutive tyrosine kinase activity not only abrogated the IL-3 requirement of the cells, but also caused them to become tumorigenic in nude athymic mice. The gain-of-function mutations of c-kit receptor appear to result in the malignant transformation of mast cells. Taken together, the signals from the c-kit receptor are essential for the development, survival, and malignant transformation of mast cells.
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PMID:Role of c-kit receptor tyrosine kinase in the development, survival and neoplastic transformation of mast cells. 911 Mar 44


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