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)

Cross-linking the high affinity IgE receptor Fc epsilonRI of basophils and mast cells activates receptor-associated protein-tyrosine kinases and stimulates a signaling cascade leading to secretion, ruffling, spreading, and cytokine production. Previous evidence that the pan-prenylation inhibitor lovastatin blocks Ag-stimulated Ca2+ influx, secretion, and membrane/cytoskeletal responses implicated isoprenylated proteins in the Fc epsilonRI-coupled signaling cascade but could not distinguish between contributions of C15 (farnesylated) and C20 (geranylgeranylated) species. Here we establish concentrations of lovastatin and the farnesyl-specific inhibitor BZA-5B that inhibit the farnesylation and Ag-induced activation of Ras species in RBL-2H3 cells (H-Ras, K-RasA, and K-RasB). These inhibitors have little effect on tyrosine kinase activation, which initiates Fc epsilonRI signaling. Although Ras is disabled, only lovastatin substantially blocks Raf-1 activation, and neither inhibitor affects mitogen-activated protein kinase kinase/extracellular signal regulated kinase kinase (MEK) or ERK1/ERK2 activation. Thus, the pathway to Fc epsilonRI-mediated MEK/ERK and ERK activation can apparently bypass Ras and Raf-1. Predictably, only lovastatin inhibits Ag-induced ruffling, spreading, and secretion, previously linked to geranylgeranylated Rho and Rab family members. Additionally, only lovastatin inhibits phospholipase Cgamma-mediated inositol (1,4,5) trisphosphate production, sustained Ca2+ influx, and Ca2+-dependent IL-4 production, suggesting novel roles for geranylgeranylated (lovastatin-sensitive, BZA-5B-insensitive) proteins in Fc epsilonRI signal propagation. Remarkably, BZA-5B concentrations too low to inactivate Ras reduce the lag time to Ag-induced Ca2+ stores release and enhance secretion. These results link a non-Ras farnesylated protein(s) to the negative regulation of Ca2+ release from intracellular stores and secretion. We identified no clear role for Ras in Fc epsilonRI-coupled signaling but suggest its involvement in mast cell growth regulation based on the inhibition of cell proliferation by both BZA-5B and lovastatin.
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PMID:MEK and ERK activation in ras-disabled RBL-2H3 mast cells and novel roles for geranylgeranylated and farnesylated proteins in Fc epsilonRI-mediated signaling. 986 3

Aggregation of the high-affinity immunoglobulin E (IgE) receptor (FcepsilonRI) on mast cells induces a number of biochemical events, including protein-tyrosine phosphorylation leading to degranulation and multiple cytokine gene transcription. Here, we have demonstrated that a second member of the Cbl family of ubiquitin-protein ligase Cbl-b translocates into the lipid raft after FcepsilonRI engagement. Overexpression of Cbl-b in the lipid raft inhibits FcepsilonRI-mediated degranulation and cytokine gene transcription through the distinct mechanism. A point mutation of Cys373 in the RING finger domain of Cbl-b abrogates the suppression of FcepsilonRI-mediated degranulation but not cytokine gene transcription. The antigen-induced tyrosine phosphorylation of FcepsilonRI, Syk, phospholipase C-gamma (PLC-gamma), activation of c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK), inhibitor of nuclear factor kappaB kinase (IKK), and Ca++ influx were all suppressed in the cells overexpressing Cbl-b in the lipid raft. In particular, the expression amount of Gab2 protein and thereby its FcepsilonRI-mediated tyrosine phosphorylation were dramatically down-regulated by ubiquitin-protein ligase activity of Cbl-b. These results suggest that Cbl-b is a negative regulator of both Lyn-Syk-LAT and Gab2mediated complementary signaling pathways in FcepsilonRI-mediated mast cell activation.
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PMID:Negative regulation of FcepsilonRI-mediated mast cell activation by a ubiquitin-protein ligase Cbl-b. 1460 64

Recently we have isolated four active components from Tanshen (the root of Salvia miltiorrhiza Bunge, Labiatae) responsible for the anti-allergic activities. In this study, the molecular mechanism of action of tanshinones for the inhibition of mast cell degranulation was investigated by testing their effects on the signaling components of the high affinity IgE receptor FcepsilonRI. Activation of FcepsilonRI produced immediate tyrosine phosphorylation of Syk, mitogen-activated protein kinase extracellular signal-regulated kinase, ERK1/ERK2 (p44, p42), and phospholipase Cgamma2 (PLCgamma2). 5,16-Dihydrotanshinone-I possessed the strongest inhibitory effects on mast cell degranulation and markedly reduced FcepsilonRI-mediated tyrosine phosphorylation of ERK and PLCgamma2. This suggests that tanshinones possibly exert their anti-allergic activities by affecting FcepsilonRI-mediated tyrosine phosphorylation of ERK and PLCgamma2. Abbreviations. FcepsilonRI:high affinity IgE receptor ERK:extracellular signal regulated kinase PLC: phospholipase C
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PMID:Tanshinones inhibit mast cell degranulation by interfering with IgE receptor-mediated tyrosine phosphorylation of PLCgamma2 and MAPK. 1499 99

Adaptor protein 3BP2 positively regulates the high affinity IgE receptor (FcepsilonRI)-mediated activation of degranulation in mast cells. Genetic study identified the point mutations of 3BP2 gene in human-inherited disease cherubism. The multiple cysts in cherubism lesion of jaw bones are filled with the activated osteoclasts and stromal cells, including mast cells. By over-expression study using rat basophilic leukaemia RBL-2H3 mast cells, we have analysed the effect of the point mutations on the function of 3BP2 protein, which plays a positive regulatory role on FcepsilonRI-mediated mast cell activation. Over-expression of 3BP2 mutants suppressed the antigen-induced degranulation and cytokine gene transcription. Antigen-induced phosphorylation of Vav1, activation of Rac1, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen activated protein kinase (MAPK), inhibitor of nuclear factor kappaB kinase (IKK) and nuclear factor of activated T cells (NFAT) were all impaired in the cells over-expressing the cherubism mutants of 3BP2. Furthermore, cherubism mutations of 3BP2 may abrogate the binding ability to interact with chaperone protein 14-3-3. These results demonstrate that over-expression of the mutant form of 3BP2 inhibits the antigen-induced mast cell activation. It suggests that point mutations of 3BP2 gene cause the dysfunction of 3BP2 in vivo.
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PMID:Point mutations of 3BP2 identified in human-inherited disease cherubism result in the loss of function. 1550 12

Mast cells play a key role in allergic inflammation by releasing various mediators, such as histamine, serotonin, leukotrienes and cytokines. A signaling cascade of events activated by stimulation with antigens contributes to the regulation of mast cell degranulation. While various anti-inflammatory and anti-allergic drugs have been developed that inhibit degranulation of mast cells, the inhibitory mechanism has been poorly understood. Licochalcone A (Lico A) is a retrochalcone isolated from the root of Xinjiang liquorice and has been reported to exhibit various biological activities such as anti-inflammatory activity. We examined the effects of Lico A and related chalcones on degranulation in a rat basophilic leukemia cell line, RBL-2H3. Whereas Lico A and licochalcone C (Lico C) exhibited inhibitory activity with cytotoxicity, licochalcone D (Lico D) significantly inhibited the degranulation in RBL-2H3 cells with low cytotoxicity. Moreover, Lico D significantly inhibited the Ca2+ influx and phosphorylation of extracellular signal regulated kinase (ERK) and MEK. These results suggest that Lico D inhibits mast cell degranulation via the inhibition of both extracellular Ca2+ influx and activation of the MEK-ERK pathway.
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PMID:Licochalcones suppress degranulation by decreasing the intracellular Ca2+ level and tyrosine phosphorylation of ERK in RBL-2H3 cells. 2039 8

S100A8 is implicated in the pathogenesis of inflammatory diseases. S100A8 is upregulated in macrophages by Toll-like receptors (TLR)-3, 4, and 9 agonists in an IL-10-dependent manner, and by corticosteroids in vitro and in vivo, and scavenges oxidants generated by activated phagocytes. Because if its elevated expression in various lung disorders, we asked whether S100A8 was protective in allergic inflammation. S100A8, but not Cys(41)-Ala S100A8, in which the single reactive Cys residue was replaced by Ala, reduced mast cell (MC) degranulation and production of particular cytokines (IL-6, IL-4, and granulocyte macrophage colony-stimulating factor) in response to IgE-crosslinking in vitro, likely by inhibiting intracellular reactive oxygen species production, thereby reducing downstream linker for activation of T cells and extracellular signal regulated kinase/mitogen-activated protein kinase phosphorylation. In lungs of mice with acute asthma, S100A8, but not Cys(41)-Ala S100A8, reduced MC degranulation, production of eosinophil chemoattractants (IL-5, eotaxin, and monocyte chemoattractant protein-1), and eosinophil infiltration. Suppression of IL-6 and IL-13 could have contributed to reduced mucus production seen in lungs of S100A8-treated mice. IgE production was unaffected. In asthma, there is an imbalance of anti-oxidant systems that are generally protective. Our results strongly support a protective role for S100A8 in allergic inflammation by modulating MC activation and eosinophil recruitment, and by scavenging oxidants generated by activated leukocytes, in processes reliant on its thiol-scavenging capacity.
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PMID:S100A8 modulates mast cell function and suppresses eosinophil migration in acute asthma. 2114 8

The pathogenesis of interstitial cystitis/painful bladder syndrome (IC/PBS) is multifactorial, but likely involves urothelial cell dysfunction and mast cell accumulation in the bladder wall. Activated mast cells in the bladder wall release several inflammatory mediators, including histamine and tryptase. We determined whether mitogen-activated protein (MAP) kinases are activated in response to tryptase stimulation of urothelial cells derived from human normal and IC/PBS bladders. Tryptase stimulation of normal urothelial cells resulted in a 2.5-fold increase in extracellular signal regulated kinase 1/2 (ERK 1/2). A 5.5-fold increase in ERK 1/2 activity was observed in urothelial cells isolated from IC/PBS bladders. No significant change in p38 MAP kinase was observed in tryptase-stimulated normal urothelial cells but a 2.5-fold increase was observed in cells isolated from IC/PBS bladders. Inhibition of ERK 1/2 with PD98059 or inhibition of p38 MAP kinase with SB203580 did not block tryptase-stimulated iPLA2 activation. Incubation with the membrane phospholipid-derived PLA2 hydrolysis product lysoplasmenylcholine increased ERK 1/2 activity, suggesting the iPLA2 activation is upstream of ERK 1/2. Real time measurements of impedance to evaluate wound healing of cell cultures indicated increased healing rates in normal and IC/PBS urothelial cells in the presence of tryptase, with inhibition of ERK 1/2 significantly decreasing the wound healing rate of IC/PBS urothelium. We conclude that activation of ERK 1/2 in response to tryptase stimulation may facilitate wound healing or cell motility in areas of inflammation in the bladder associated with IC/PBS.
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PMID:Tryptase activation of immortalized human urothelial cell mitogen-activated protein kinase. 2392 67