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 present study was conducted to examine the effects of two protein tyrosine kinase inhibitors, genistein and tyrphostin 47, on an in vitro model of allergic asthma. Guinea pigs were sensitized with purified IgG raised against ovalbumin (OA). Isolated sensitized bronchial rings contracted in response to OA in a concentration-dependent manner, maximum contraction being achieved at 1 microg/ml. Genistein and tyrphostin 47 concentration-dependently (10-100 microM) inhibited OA-induced anaphylactic contraction of the bronchi, as well as release of histamine and peptidoleukotrienes from chopped lung preparations. Genistein, but not tyrphostin 47, significantly suppressed bronchial contraction to leukotriene D4 at 50 microM and to histamine at 100 microM. Daidzein, an inactive congener of genistein, did not alter OA-induced anaphylactic contraction. However, it slightly reduced bronchial contraction to leukotriene D4 and the OA-stimulated release of peptidoleukotrienes. The inhibitory effects were significantly weaker than those of genistein. Taken together, our results show that tyrphostin 47 inhibited anaphylactic contraction mainly by preventing mast cell degranulation, whereas genistein exerted inhibitory effects partly by blocking mast cell degranulation and partly by attenuating leukotriene D4-induced bronchial contraction. These findings suggest that protein tyrosine kinase inhibitors have a therapeutic potential as mast cell stabilizers in the treatment of allergic diseases such as bronchial asthma.
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PMID:Effects of tyrosine kinase inhibitors on antigen challenge of guinea pig lung in vitro. 933 17

Aggregation of the high affinity IgE receptor (Fc epsilonRI), a member of the immune receptor family, results in the activation of protein tyrosine kinases and downstream signaling pathways. The two cytoplasmic Src homology 2 domain-containing protein tyrosine phosphatases, SHP-1 (also called SH-PTP1, PTP1C or HCP) and SHP-2 (also known as SH-PTP2, PTP1D, PTP2C, or Syp), are expressed in the RBL-2H3 rat mast cell line. Here we report that aggregation of Fc epsilonRI induced the tyrosine phosphorylation of both SHP-1 and SHP-2. This phosphorylation was independent of the presence of the protein tyrosine kinase Syk. Both SHP-1 and SHP-2 associated with Fc epsilonRI. Whereas SHP-1 was constitutively associated with the receptor, SHP-2 coprecipitated with Fc epsilonRI only after receptor aggregation. Fusion proteins containing either the full-length or the Src homology 2 domains of SHP-2 directly bound to the tyrosine-phosphorylated beta, but not the gamma, subunit of Fc epsilonRI. In the reciprocal experiments, synthetic phosphorylated peptides based on the immunoreceptor tyrosine-based activation motif of the beta, but not the gamma, subunit precipitated SHP-2. In contrast, neither fusion proteins nor synthetic peptides detected interaction between SHP-1 and Fc epsilonRI. In vitro, both SHP-1 and SHP-2 dephosphorylated tyrosine-phosphorylated beta and gamma subunits of Fc epsilonRI. Therefore, SHP-1 and SHP-2 associate with Fc epsilonRI by different mechanisms and can regulate the extent of the tyrosine phosphorylation of the receptor subunits. Thus, unlike other immune cells in which inhibitory molecules are recruited by accessory proteins, Fc epsilonRI bind molecules that both activate and inhibit signal transduction.
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PMID:Syk-independent tyrosine phosphorylation and association of the protein tyrosine phosphatases SHP-1 and SHP-2 with the high affinity IgE receptor. 937 41

The protein tyrosine kinase Syk plays a pivotal role in mediating the high-affinity IgE receptor (Fc epsilonRI)-induced degranulation of mast cells. To examine the mechanism of Syk regulation, the two tyrosine residues at 519 and 520 in the putative activation loop of rat Syk were mutated to phenylalanine either singly or in combination. The various mutants were expressed in a Syk-negative variant of the RBL-2H3 (rat basophilic leukemia 2H3) mast cell line. In these transfected cell lines, mutant Syk did show increased tyrosine phosphorylation in vivo and increased enzymatic activity in vitro after Fc epsilonRI aggregation. There were conformational changes detected by an Ab when the wild-type and mutant Syk were either tyrosine phosphorylated or bound to tyrosine-phosphorylated immunoreceptor tyrosine-based activation motif peptides. However, these mutant Syk were incapable of transducing Fc epsilonRI signaling. In cells in which the expression level of mutant Syk was similar to that of the wild-type Syk, Fc epsilonRI cross-linking induced no increase in cellular protein tyrosine phosphorylation, no increase in tyrosine phosphorylation of phospholipase C-gamma2 and mitogen-activated protein kinase, and no histamine release. Overexpression of Y519F or Y520F Syk mutants partially reconstituted the signaling pathways. These results indicate that these tyrosines in the putative activation loop are not essential for the enzymatic activity of Syk or for the conformational changes induced by binding of tyrosine-phosphorylated immunoreceptor tyrosine-based activation motif peptides. However, these tyrosines are necessary for Syk-mediated propagation of Fc epsilonRI signaling.
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PMID:Mutations in the activation loop tyrosines of protein tyrosine kinase Syk abrogate intracellular signaling but not kinase activity. 978 Feb 14

It has been shown that activation of protein tyrosine kinases (PTKs) is the earliest detectable signaling response to FcepsilonRI cross-linking on mast cells. Following tyrosine kinase activation, a family of mitogen-activated protein kinases (MAPKs) was found to be activated as well. Activation of this PTK signaling cascade will lead to mast cell degranulation. This review summarizes our recent studies on the role of PTK signaling cascade in an in vitro guinea pig model of allergic asthma using PTK inhibitors, genistein and tyrphostin 47, and MAPK kinase inhibitor, PD098059. Inhibitors of the PTK and MAPK signaling pathways significantly attenuated the ovalbumin (OVA)-induced bronchial anaphylactic contraction and enhanced relaxation of constricted airways, respectively, and substantially blocked the release of histamine and peptidoleukotrienes from chopped lung preparations induced by OVA. Based upon their substantial inhibitory effects on the Schultz-Dale reaction, further examination on the potential anti-asthmatic effects of PTK cascade inhibitors in an in vivo model of allergic asthma is recommended.
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PMID:Effects of inhibitors of the tyrosine kinase signaling cascade on an in vitro model of allergic airways. 1069 63

Activation of nontransmembrane protein tyrosine kinases (PTKs), phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) has been shown to be responsible for high-affinity Fc receptor (Fcepsilon RI)-mediated mast cell degranulation. Effects of inhibitors of the PTK signaling cascade on ovalbumin (OA)-induced anaphylactic contraction of isolated guinea-pig bronchi and release of histamine and peptidoleukotrienes from chopped lung preparations were studied. Genistein (30 microM) and tyrphostin 47 (50 microM), two PTK inhibitors, as well as LY294002 (10 microM), a selective PI3K inhibitor, significantly reduced (p < 0.05) peak anaphylactic bronchial contraction and facilitated relaxation of the contracted bronchi. PD 098059 (30 microM), a selective MAPK kinase inhibitor, failed to suppress OA-induced peak bronchial contraction, but facilitated the relaxation of the contracted bronchi (p < 0.05). At the same concentrations, none of these inhibitors showed any inhibitory effects on histamine-, leukotriene D(4) (LTD(4))- or KCl-induced bronchial contraction. On the other hand, these inhibitors significantly prevented (p < 0.05) OA-induced release of both histamine and peptidoleukotrienes from chopped lung preparations. In addition, combined PD 098059 and LY294002 treatment markedly (p < 0.05) suppressed the peak anaphylactic bronchial contraction and facilitated relaxation of the contracted bronchi. The combination of these two inhibitors further inhibited the release of peptidoleukotrienes from chopped lung preparations. Taken together, our data show that inhibition of tyrosine kinase signaling cascade can markedly attenuate anaphylactic contraction of airways, probably via inhibition of mast cell degranulation, and that inhibitors of this signaling cascade may have therapeutic potential for the treatment of asthma.
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PMID:Inhibitors of tyrosine kinase signaling cascade attenuated antigen challenge of guinea-pig airways in vitro. 1090 31

Aggregation of the high-affinity IgE receptor induces the tyrosine phosphorylation of subunits of the receptor and the subsequent association with the receptor of the cytosolic protein tyrosine kinase Syk. The current experiments examined the functional importance of membrane association of Syk and the role of the SH2 domain in receptor-mediated signal transduction. Wild-type Syk and chimeric Syk molecules with the c-Src myristylation sequence at the amino-terminus were expressed in a Syk-negative mast cell line. Chimeric Syk with the myristylation sequence was membrane associated, and a small fraction was constitutively colocalized with FcepsilonRI, Lyn, and LAT (linker for T-cell activation) in the glycolipid-enriched microdomains or rafts. However, even under these conditions, the tyrosine phosphorylation of Syk and the downstream propagation of signals required FcepsilonRI aggregation. This chimeric Syk was less active than wild-type Syk in FcepsilonRI-mediated signal transduction. In contrast, a truncated membrane-associated form of Syk that lacked the SH2 domains was not tyrosine phosphorylated by receptor aggregation and failed to transduce intracellular signals. These findings suggest that SH2 domain-mediated membrane translocation of Syk is essential for the FcepsilonRI-mediated activation of Syk for downstream signaling events leading to histamine release. Furthermore, the localization of Syk in glycolipid-enriched microdomains by itself is not enough to generate or enhance signaling events.
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PMID:SH2 domain-mediated targeting, but not localization, of Syk in the plasma membrane is critical for FcepsilonRI signaling. 1122 80

The mast cell function-associated Ag (MAFA) is a type II membrane glycoprotein originally found on the plasma membrane of rat mucosal-type mast cells (RBL-2H3 line). A C-type lectin domain and an immunoreceptor tyrosine-based inhibitory motif (ITIM) are located in the extracellular and intracellular domains of MAFA, respectively. MAFA clustering has previously been shown to suppress the secretory response of these cells to the FcepsilonRI stimulus. Here we show that the tyrosine of the ITIM undergoes phosphorylation, on MAFA clustering, that is markedly enhanced on pervanadate treatment of the cells. Furthermore, the Src homology 3 domain of the protein tyrosine kinase Lyn binds directly to a peptide containing nonphosphorylated MAFA ITIM and PAAP motif. Results of both in vitro and in vivo experiments suggest that Lyn is probably responsible for this ITIM phosphorylation, which increases the Src homology domain 2 (SH2) affinity of Lyn for the peptide. In vitro measurements established that tyrosine-phosphorylated MAFA ITIM peptides also bind the SH2 domains of inositol 5'-phosphatase (SHIP) as well as protein tyrosine phosphatase-2. However, the former single domain is bound 8-fold stronger than both of the latter. Further support for the role of SHIP in the action of MAFA stems from in vivo experiments in which tyrosine-phosphorylated MAFA was found to bind primarily SHIP. In RBL-2H3 cells overexpressing wild-type SHIP, MAFA clustering causes markedly stronger inhibition of the secretory response than in control cells expressing normal SHIP levels or cells overexpressing either wild-type protein tyrosine phosphatase-2 or its dominant negative form. In contrast, on overexpression of the SH2 domain of SHIP, the inhibitory action of MAFA is essentially abolished. Taken together, these results suggest that SHIP is the primary enzyme responsible for mediating the inhibition by MAFA of RBL-2H3 cell response to the FcepsilonRI stimulus.
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PMID:SH2 domain-containing inositol polyphosphate 5'-phosphatase is the main mediator of the inhibitory action of the mast cell function-associated antigen. 1171 5

Although the area of research on the role of MCs in innate immunity is relatively new, a number of studies that are reviewed here provide substantial evidence that MCs play a critical role in host immune defense against gram-negative bacteria. The studies show that mast cells have the ability to recognize and engulf bacteria and they release a number of inflammatory mediators including interleukin (IL)-4, IL-6, IL-10, TNF alpha, and leukotrienes in response to bacterial challenge. MC-derived TNF alpha and leukotrienes are shown to be important for bacterial clearance and early recruitment of phagocytic help at the site of infection. Studies directed at elucidating the molecular mechanisms associated with mast cell recognition of bacteria and subsequent events leading to mast cell mediator release revealed that GPI anchored CD48 molecule present on the cell surface of mast cells serves as a receptor for the bacterial adhesion molecule, FimH. The ligation of CD48 receptor by FimH-expressing bacteria results in bacterial uptake into caveolar chambers. This distinct mechanism of bacterial uptake promotes bacterial survival inside the cytosol of the mast cells. Although the exact mechanism(s) of how MC-dependent inflammatory responses are regulated is currently not known, recent studies have shown that complement, CD11 beta/CD18 (Mac-1) and protein tyrosine kinase JAK3, and TLR4 are important for the full expression of MC-dependent innate immunity in mice.
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PMID:Regulation of mast cell-mediated innate immunity during early response to bacterial infection. 1197 23

FcgammaRIIB are single-chain low-affinity receptors for the Fc portion of IgG antibodies that are widely expressed by hematopoietic cells including mast cells. We previously demonstrated that FcgammaRIIB negatively regulate cell activation triggered by receptors that possess Immunoreceptor Tyrosine-based Activation Motifs (ITAMs) including high-affinity IgE receptors (FcepsilonRI). FcgammaRIIB possess an Immunoreceptor Tyrosine-based Inhibition Motif (ITAM) whose deletion or mutation abolishes inhibition. When coaggregated with FcepsilonRI, the FcgammaRIIB ITIM is tyrosyl-phosphorylated by the src family protein tyrosine kinase lyn, and recruits the SH2 domain-containing inositol 5-phosphatase SHIP that accounts for inhibition of cell activation. We found recently that, when coaggregated with Kit, FcgammaRIIB can also inhibit mast cell proliferation: thymidine incorporation is inhibited, cells do not enter the G1 phase of the cell cycle, the induction of cyclins D2, D3 and A is inhibited, the activation of the MAP kinases Erk1/2, JNK and p38 is decreased, Akt phosphorylation is inhibited, and SHIP coprecipitates with FcgammaRIIB. Although inhibition of Akt phosphorylation and Erk activation was abrogated in SHIP(-/-) cells, inhibition of thymidine incorporation was only partially reduced. FcgammaRIIB-dependent inhibition of Kit-mediated mast cell proliferation was however mimicked by FcgammaRIIB whose intracytoplasmic domain was replaced by the catalytic domain of SHIP. We also found that FcgammaRIIB can inhibit the proliferation of cells whose proliferation was rendered growth factor-independent because they express a mutated form of Kit that renders this RTK constitutively activated. Based on these results we developed models aiming at using FcgammaRIIB as targets for new therapeutic approaches of disease associated with mast cell activation such as allergies and diseases associated with mast cell proliferation such as mastocytosis, mastocytomas or mast cell leukemias.
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PMID:Negative regulation of mast cell proliferation by FcgammaRIIB. 1221 98

Previous investigators have reported that deletion of the protein tyrosine kinase Lyn alters mast cell (MC) signaling responses but does not affect or reduces the cytokine-mediated proliferation of mouse bone marrow-derived MC (BMMC) precursors and of mature MC. We observed that Lyn-deficient mice have more peritoneal MC than wild-type (WT) mice. Studies to explore this unexpected result showed that Lyn(-/-) BM cells expand faster than WT cells in response to interleukin (IL)-3 and stem-cell factor over the 4-5 weeks required to produce a >95% pure population of granular, receptor with high affinity for immunoglobulin E-positive BMMC. Furthermore, differentiated Lyn(-/-) BMMC continue to proliferate more rapidly than WT BMMC and undergo less apoptosis in response to cytokine withdrawal. Additionally, Lyn(-/-) BMMC support greater IL-3-mediated phosphorylation of the prosurvival kinase, Akt, and the proliferative kinase, extracellular-regulated kinase 1/2. These results identify Lyn as a negative regulator of murine MC survival and proliferation.
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PMID:The Src kinase Lyn is a negative regulator of mast cell proliferation. 1452 64


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