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 IgE receptor (FcepsilonRI) in a mast cell line resulted in activation of the p42 and the stress-activated p38 mitogen-activated protein (MAP) kinases. Selective inhibition of these respective kinases with PD 098059 and SB 203580 indicated that p42 MAP kinase, but not p38 MAP kinase, contributed to the production of the cytokine, tumor necrosis factor-alpha, and the release of arachidonic acid in these cells. Neither kinase, however, was essential for FcepsilonRI-mediated degranulation or constitutive production of tumor growth factor-beta. Studies with SB 203580 and the p38 MAP kinase activator anisomycin also revealed that p38 MAP kinase negatively regulated activation of p42 MAP kinase and the responses mediated by this kinase.
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PMID:Mitogen-activated protein (MAP) kinase regulates production of tumor necrosis factor-alpha and release of arachidonic acid in mast cells. Indications of communication between p38 and p42 MAP kinases. 914 63

Stimulation of RAW 264.7 cells with the Ca(2+)-ATPase inhibitor thapsigargin increased histamine production. Immunoblot analyses revealed that thapsigargin increased the expression of 74-kDa histidine decarboxylase protein although rat mast cell line RBL-2H3 cells express both 74- and 53-kDa histidine decarboxylase proteins. The inhibition of histamine production by the mitogen-activated protein kinase-extracellular signal-regulated kinase kinase (MEK) inhibitors PD98059 (2'-amino-3'-methoxyflavone) and U0126 (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene) and by the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole) was correlated with the inhibition of the expression of thapsigargin-induced 74-kDa histidine decarboxylase protein. The synthetic glucocorticoid dexamethasone inhibited thapsigargin-induced histamine production and 74-kDa histidine decarboxylase protein expression. The thapsigargin-induced activation of p42/p44 MAP kinase and p38 MAP kinase was also inhibited by dexamethasone. These findings indicate that the induction of histamine production by thapsigargin in RAW 264.7 cells is due to the increased expression of 74-kDa histidine decarboxylase protein and that dexamethasone inhibits thapsigargin-induced histidine decarboxylase protein expression and histamine production via inhibition of MAP kinase activation.
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PMID:Expression of 74-kDa histidine decarboxylase protein in a macrophage-like cell line RAW 264.7 and inhibition by dexamethasone. 1133 61

Stem cell factor (SCF) can be considered a cardinal cytokine in mast cell biology as it affects mast cell differentiation, survival, and migration. The objective of this study was to investigate the role of two mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK) and p38, in SCF-induced cell migration. This was examined in mouse mast cells by using PD 098059 and SB203580, which are specific inhibitors of mitogen-induced extracellular kinase (MEK) and p38 MAP kinase, respectively. SCF induced a rapid and transient activation of ERK and p38 in a dose-dependent manner. Inhibition of p38 activity by SB203580 was paralleled with a marked reduction of migration toward SCF, whereas the effect of the MEK inhibitor was less pronounced. This is the first report of a physiological function of SCF-dependent activation of p38. Whether p38-mediated mast cell migration is a possible target for suppression of mast cell hyperplasia remains to be determined.
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PMID:Stem cell factor-induced migration of mast cells requires p38 mitogen-activated protein kinase activity. 1141 47

Transforming growth factor-beta (TGF-beta) isoforms regulate numerous cellular functions through binding to receptors with intrinsic serine/threonine kinase activity that transduce the intracellular signals via activation of Smad proteins. In this study, we examined the signalling pathways involved in TGF-beta1-mediated growth inhibition and migration in a human mast cell line, HMC-1. TGF-beta1 evoked optimal migration at 40 fM, whereas maximal growth inhibition was obtained at 400 pM. Protein tyrosine kinase inhibitors completely inhibited TGF-beta1-mediated migration, without affecting the antimitogenic response. Smad2 was phosphorylated upon TGF-beta1 treatment, both in the absence and presence of genistein. The mitogen-induced extracellular kinase (MEK) inhibitor, PD98059, blocked the migratory response without affecting growth inhibition. In contrast, the p38 MAP kinase inhibitor, SB203580, had no significant effect on either migration or growth inhibition. These results indicate that different signalling pathways mediate TGF-beta1-induced migration and growth inhibition in HMC-1 cells, where the migration involves MEK activity.
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PMID:Transforming growth factor-beta-mediated mast cell migration depends on mitogen-activated protein kinase activity. 1151 23

Mast cells play important roles in inflammation and immunity and express the high-affinity immunoglobulin E receptor (Fc epsilon RI) and the receptor protein-tyrosine kinase Kit. Aggregation of Fc epsilon RI via antigen binding elicits signals leading to the release of preformed inflammatory mediators as well as de novo-synthesized lipid mediators and cytokines and to elevated cell adhesion and migration. Here, we report that in mouse bone marrow-derived mast cells, Fer kinase is activated downstream of activated Fc epsilon RI and activated Kit receptor, and this activation is abolished in cells homozygous for a kinase-inactivating mutation in Fer (fer(DR/DR)). Interestingly, the highly related Fps/Fes kinase is also activated upon Fc epsilon RI aggregation. This report represents the first description of a common signaling pathway activating Fer and Fps/Fes. While Fer-deficient cells showed similar activation of the Erk mitogen-activated protein (MAP) kinases, p38 MAP kinase activation was less sustained than that in wild-type cells. Although no major defects were observed in degranulation, leukotriene biosynthesis, and cytokine secretion, Fer-deficient cells displayed increased adhesion and decreased motility upon activation of Fc epsilon RI and the Kit receptor. The restoration of Fer kinase activity in fer(DR/DR) mast cells resulted in prolonged p38 kinase activation and increased antigen-mediated cell migration of sensitized mast cells. Thus, Fer is required for maximal p38 kinase activation to promote the chemotaxis of activated mast cells. Further studies with mast cells derived from fps/fes-deficient mice will be required to provide insight into the role of Fps/Fes in mast cell activation.
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PMID:Fer kinase is required for sustained p38 kinase activation and maximal chemotaxis of activated mast cells. 1219 36

Trypsin activating both proteinase-activated receptor (PAR) 2 and PAR4 plays an important role in inflammation. We have investigated the potential of trypsin to induce TNF-alpha secretion from the human leukemic mast cell line (HMC-1). HMC-1 cells co-express both PAR2 and PAR4, and their agonist trypsin signals to HMC-1 cells. Trypsin (100 nm), SLIGKV-NH(2) (100 microm, corresponding to the PAR2 tethered ligand), or GYPGQV-NH(2) (100 microm, corresponding to the PAR4 tethered ligand) induced tumour necrosis factor (TNF)-alpha secretion from HMC-1 cells. TNF-alpha secretion by trypsin was significantly blocked by pretreatment with 50 microm PD098059, MEK-1 inhibitor. Furthermore, trypsin stimulated the activation of extracellular signal-regulated kinase (ERK) in HMC-1 cells without any detectable activation of c-Jun N-terminal kinase (JNK) and p38 MAP kinase homologue. These results show that trypsin may induce TNF-alpha secretion following activation of ERK via both PAR2 and PAR4 on HMC-1 cells.
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PMID:Trypsin induces tumour necrosis factor-alpha secretion from a human leukemic mast cell line. 1273 6

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 are able to produce a huge panel of mediators including the Th2-type cytokine IL-9, which is considered to be a key mediator for the pathogenesis of allergic asthma, but detailed information on the regulation of IL-9 transcription in mast cells has been scarce. Herein we provide evidence that the erythroid/myeloid transcription factor GATA-1, which is not expressed in Th2 cells, is a potent activator of IL-9 expression in murine bone marrow-derived mast cells (BMMC). Furthermore, in mast cells, but not in Th2 cells, production of IL-9 is sensitive to inhibition of p38 MAP kinase. As transactivation mediated by GATA-1 is also sensitive to inhibition of p38 MAP kinase, and GATA-1 is a target for p38 MAP kinase-mediated phosphorylation in vitro, we conclude that both signaling molecules represent a part of a mast cell-specific signaling network that regulates the expression of IL-9.
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PMID:p38 MAP kinase drives the expression of mast cell-derived IL-9 via activation of the transcription factor GATA-1. 1665 Aug 98

Transforming growth factor-beta (TGF-beta) modulates functions of bone marrow-derived cultured mast cells (BMMCs); cell maturation (up-regulation of mouse mast cell proteases (mmcps)), growth arrest and migration. We investigated the roles of p38 MAP kinase and Smad3 in TGF-beta-mediated cell responses in BMMCs. Treating BMMCs with TGF-beta induced the phosphorylation of p38 within 2 h and persisted for 24 h. The involvement of p38 in TGF-beta-induced cell responses depended upon mast cell functions; it was necessary for up-regulation of mmcp-1 and migration, but not for up-regulation of mmcp-7 and inhibition of metabolic activity. New protein synthesis was required for the up-regulation of mmcp-1 but not mmcp-7 in response to TGF-beta treatment, and stabilization of mRNA was partially responsible for the increase in gene transcript of mmcp-1. The decrease in metabolic activity in response to TGF-beta treatment was smaller in Smad3-deficient BMMCs compared to wild-type BMMCs. Maximal migration was detected at a TGF-beta concentration of 40 fM in wild-type BMMCs, whereas TGF-beta-induced migration was absent in Smad3-deficient BMMCs. Thus, the roles of p38 and Smad3 are different among TGF-beta-mediated cell responses in BMMCs.
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PMID:Involvement of p38 MAP kinase and Smad3 in TGF-beta-mediated mast cell functions. 1675 Sep 2

Mast cells have the ability to react to multiple stimuli, implicating these cells in many immune responses. Specific signals from the microenvironment in which mast cells reside can activate different molecular events that govern distinct mast cells responses. We previously demonstrated that hydrogen peroxide (H(2)O(2)) promotes IL-4 and IL-6 mRNA production and potentates FcepsilonRI-induced cytokine release in rat basophilic leukemia RBL-2H3 cells. To further evaluate the effect of an oxidative microenvironment (which is physiologically present in an inflammatory site) on mast cell function and the molecular events responsible for mast cell cytokine production in this environment, we analyzed the effect of H(2)O(2) treatment on IL-4 production in bone marrow-derived, cultured mast cells. Our findings show that nanomolar concentrations of H(2)O(2) induce cytokine secretion and enhance IL-4 production upon FcepsilonRI triggering. Oxidative stimulation activates a distinct signal transduction pathway that induces Fyn/PI3K/Akt activation and the selective phosphorylation of p38 MAP kinase. Moreover, H(2)O(2) induces AP-1 and NFAT complexes that recognize the IL-4 promoter. The absence of Fyn and PI3K or the inhibition of p38 MAPK activity demonstrated that they are essential for H(2)O(2)-driven IL-4 production. These findings show that mast cells can respond to an oxidative microenvironment by initiating specific signals capable of eliciting a selective response. The findings also demonstrate the dominance of the Fyn/p38 MAPK pathway in driving IL-4 production.
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PMID:Selective activation of Fyn/PI3K and p38 MAPK regulates IL-4 production in BMMC under nontoxic stress condition. 1727 64


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