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)

Adenosine potentiates preformed mediator release from mouse bone marrow-derived mast cells stimulated with specific Ag or the calcium ionophore A23187. When these mast cells were cultured for 30 to 120 min with the phorbol ester PMA (10(-8) or 10(-7) M), protein kinase C activity was increased and Ag-stimulated beta-hexosaminidase release was modestly inhibited, whereas A23187-stimulated release was synergistically enhanced. However, in both cases, exogenous adenosine failed to augment beta-hexosaminidase release. Overnight PMA exposure produced a decrease in protein kinase C activity and a decrease in both Ag- and A23187-stimulated preformed mediator release, as well as a lack of responsiveness to adenosine. This hyporesponsiveness could be reversed by 24 h after washing the cells free of PMA. The generation of the arachidonic acid metabolite leukotriene C4 was not altered by mast cell PMA exposure. The ability of adenosine to increase intracellular cAMP concentrations was modestly blunted by high doses of PMA, and PMA abrogated the increase in intracellular free calcium levels usually observed in cells stimulated with Ag in the presence of 10(-5) M adenosine. PMA exposure induces a hyporesponsiveness to adenosine in mast cells, either by a direct effect on protein kinase C activity and/or by an effect on adenosine receptor expression or recycling.
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PMID:Pretreatment with phorbol esters abrogates mast cell adenosine responsiveness. 253 70

Rat mast cell granules were obtained by homogenization of highly purified rat mast cells and isolated in a Percoll gradient. DPI synthesis in rat mast cell granules was assayed by measuring the incorporation of 32P from [gamma 32P] ATP into DPI in the absence of exogenous phosphatidylinositol (PI). Lipids were isolated with methanol/chloroform/HC1 and were separated by thin-layer chromatography on oxalic acid impregnated silica gel plates. DPI areas were identified by staining with iodine, scraped and measured for 32P radioactivity. The addition of PMA to the granules caused an increase of DPI synthesis, which can be catalysed by PI kinase. Neither an inactive phorbol ester, 4-alpha-phorbol-12, 13-didecanoate, nor dimethyl sulfoxide (DMSO) used as a solvent for PMA had any effect. The effect of PMA in the DPI synthesis was dose-dependent and maximal effects were observed at 10-100 ng/ml. Dose-response curves of the effects of PMA in DPI synthesis in the granules corresponded to those of other biochemical effects of PMA in rat mast cells, such as mediator release mediated through the activation of protein kinase C. These results suggest that PMA may directly affect PI kinase or indirectly regulate its activity in rat mast cell granules.
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PMID:[Effect of phorbol myristate acetate (PMA) on diphosphoinositide (DPI) synthesis in rat mast cell granules]. 254 22

The role of cytoskeleton and protein phosphorylation in concanavalin A and phorbol ester (PMA) induced mast cell secretion was investigated. It was shown that the receptor coupled with lectin interacts with the cytoskeleton. When the ligand-receptor complex is formed, an increased phosphorylation of some proteins is induced. The same proteins are phosphorylated under the influence of PMA, a protein kinase C activator, thus suggesting that protein kinase C is involved in the regulation of mast cell exocytosis. The results obtained testify to the effect that the mechanism of mast cell degranulation induced by concanavalin A is due to modification of the cytoskeleton.
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PMID:[The role of protein phosphorylation in mast cell secretion, stimulated by concanavalin A. Connection to the cytoskeleton]. 259 Jun 81

The murine mast cell line PB-3c is dependent on interleukin 3 (IL-3) with respect to survival and proliferation. These cells also require IL-3 to display antigen-mediated serotonin release, which is coupled to a transient increase of cytosolic free calcium ([Ca2+]i). The antigen-mediated exocytosis is inhibited by phorbol 12-tetradecanoate 13-acetate (PTA), an activator of phospholipid/Ca2+-sensitive protein kinase. In contrast, the malignant mast cell variant PB-1 is IL-3 independent with respect to proliferation but is unable to undergo antigen-mediated exocytosis. Yet this cell line exhibits basal levels of [Ca2+]i, serotonin content, and numbers of IgE receptors comparable to those of PB-3c cells. Subcellular distribution studies revealed that the specific activity of cytosolic protein kinase C of PB-1 cells was only 40% of that found in PB-3c cells. Furthermore, the PB-1 cells showed a significantly higher specific activity of membrane-bound protein kinase C than PB-3c cells. Scatchard plot analysis of [3H]-phorbol 12,13-dibutyrate binding to intact PB-1 cells demonstrated the presence of 20% high-affinity (Kd = 6 nM) and 80% low-affinity (Kd = 60 nM) phorbol ester receptors, whereas PB-3c cells displayed only the low-affinity phorbol ester binding. Immunological characterization of protein kinase C from both cell lines revealed the presence of a normal 77-kDa protein kinase C holoenzyme in both cell lines. In addition, a 72-kDa protein kinase C-related protein band was found mainly in the membrane fraction of the PB-1 variant. It is suggested that this altered and membrane-bound form of protein kinase C may be involved in the blockage of the antigen-mediated exocytosis of PB-1 cells.
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PMID:Altered protein kinase C in a mast cell variant defective in exocytosis. 349 90

Histamine release from mast cells is intimately related with degranulation. When basic histamine releasers such as compound 48/80 were applied extracellularly to isolated rat mast cells by means of microelectrophoresis, localized degranulation was evoked near the tip of micropipet in a few seconds. In response to the second electrophoretic application at the opposite side of the membrane of the same mast cells, similar local degranulation was induced. This fact clearly indicates that local degranulation does not damage mast cells to the extent of blocking following degranulation. As intracellular electrophoretic application of compound 48/80 caused a swelling of mast cell, although no degranulation was elicited. When antigen-antibody reaction was induced in a single rat mesentery mast cell by means of microelectrophoresis, the application of antigen was made extracellularly or intracellularly. At the site of extracellular application, localized degranulation and histamine release were evoked. Histamine release was evidenced by the disappearance of histamine fluorescence in the degranulated area. Neither degranulation nor histamine release was induced by intracellular application of antigen. In freeze-fracture electronmicroscopy of the resting rat mast cells, intra-membrane particles (IMPs) were randomly distributed on the plasma membrane. When sensitized cells were exposed to antigen, IMPs were markedly dispersed so as to surround bulging regions of the membrane elicited by swollen granules. As the particles gathered at the periphery of the bulges, actually no particle was seen on the protuberant region. When rat mast cells loaded with quin 2 were exposed compound 48/80 in a Ca-free medium, a marked increase of quin 2 fluorescence was noticed, indicating that Ca2+ was released from intracellular Ca store. The binding of 45Ca was at its peak in the fractions where the highest activity of glucose-6-phosphatase, a marker enzyme for the endoplasmic reticulum, when organelles of mast cells were fractionated. This may indicate that intracellular Ca store is endoplasmic reticulum. It has been shown that microfilaments, and microtubules play some important roles in histamine release from rat mast cells. When permeabilized mast cells were stimulated with Ca2+, a translocation of protein kinase C from cytosol to membrane fraction was observed. This leads to phosphorylation of vimentin, one of intermediate filaments. In membrane skeletons of rat mast cells, alpha- and beta-fodrin, ankyrin and actin were found by means of western blotting analysis. It was supposed that membrane skeleton may be useful as a barrier between the plasma membrane and the granule membrane.
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PMID:[Development of the research in the field of histamine release]. 751 63

Bruton tyrosine kinase (EC 2.7.1.112) [Btk, encoded by Btk in mice and BTK in humans (formerly known as atk, BPK, or emb)], which is variously mutated in chromosome X-linked agammaglobulinemia patients and X-linked immunodeficient (xid) mice, has the pleckstrin homology (PH) domain at its amino terminus. The PH domain of Btk expressed as a bacterial fusion protein directly interacts with protein kinase C in mast cell lysates. Evidence was obtained that Btk is physically associated with protein kinase C in intact murine mast cells as well. Both Ca(2+)-dependent (alpha, beta I, and beta II) and Ca(2+)-independent protein kinase C isoforms (epsilon and zeta) in mast cells interact with the PH domain of Btk in vitro, and protein kinase C beta I is associated with Btk in vivo. Btk served as a substrate of protein kinase C, and its enzymatic activity was down-regulated by protein kinase C-mediated phosphorylation. Furthermore, depletion or inhibition of protein kinase C with pharmacological agents resulted in an enhancement of the tyrosine phosphorylation of Btk induced by mast cell activation.
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PMID:The pleckstrin homology domain of Bruton tyrosine kinase interacts with protein kinase C. 752 30

The present study was performed to investigate the histamine-releasing activity of non-immunological stimuli on cultured mast cell lines in comparison to isolated skin mast cells and basophils as human therapeutic target cells. The ionophore A23187 induced a dose dependent histamine release from all cell populations (enzymatically isolated human skin mast cells, human peripheral basophils and rat basophilic leukemia cells, RBL-1 and RBL-2H3). The lectin concanavalin A and the tripeptide formyl-methionyl-leucyl-phenylalanine activated only basophils, while the neural mediator substance P and compound 48/80 were active only in experiments with skin mast cells. Activators of protein kinase C (different phorbol esters and the non-phorbol mezerein) induced direct histamine release only from basophils. The data provide further evidence for heterogeneity of mast cells and indicate different signal transduction mechanisms following non-immunological activation.
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PMID:Functional comparison of different histamine-containing IgE-receptor positive cells. 752 49

Receptor tyrosine kinases are known to be important in growth and differentiation. We have recently found that c-kit, the tyrosine kinase receptor for steel factor, also regulates cell-matrix adhesion. Because Steel factor helps regulate cell migration and localization, this may be an important biologic function. Integrin adhesiveness is regulated within minutes by c-kit. The signaling pathways for tyrosine kinase stimulation of integrin adhesiveness and their relation to pathways that regulate growth and differentiation over much longer time periods remain uncharacterized. We have studied the effector pathways by which receptor tyrosine kinases regulate cell-matrix adhesion using wild-type and mutant forms of the platelet-derived growth factor (PDGF) receptor, which is closely related to c-kit. The PDGF receptor expressed in mast cells is as potent as c-kit in stimulating adhesion to fibronectin. We show that induction of adhesion is regulated through two independent pathways of phosphatidylinositol 3 kinase (PI3K) and phospholipase C-gamma 1 (PLC gamma)-protein kinase C by elimination of autophosphorylation sites required for activation of PI3K and PLC gamma or in combination with downregulation of protein kinase C or wortmannin. By contrast, a receptor mutated in both the PI3K and PLC gamma association sites can still stimulate mast cell growth, indicating a crucial role of these effector molecules in regulating adhesion rather than cell growth.
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PMID:Receptor tyrosine kinase stimulates cell-matrix adhesion by phosphatidylinositol 3 kinase and phospholipase C-gamma 1 pathways. 754 20

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

Adherence of cells to the extracellular matrix via focal adhesions is known to modulate many cellular functions. However, the role of focal adhesions in the regulation of secretion is unclear. To examine this we have used the RBL-2H3 rat mast cell line, in which we and others have observed cytoskeletal rearrangements and increased cell spreading during secretion. All activators of secretion examined, whether acting specifically through or bypassing the IgE-receptor, induced the assembly of focal adhesions, as defined by the localization of vinculin and talin. The extent of focal adhesion formation correlated with the extent of secretion and the time course of secretion also correlated with that of the assembly of focal adhesions. To examine the mechanism by which focal adhesion formation occurred, the protein kinase C inhibitor bisindolylmaleimide was used. Bisindolylmaleimide caused complete inhibition of both secretion and focal adhesion formation induced by antigen or the calcium ionophore A23187. Although PMA did not induce secretion, it induced focal adhesion assembly which was inhibited by bisindolylmaleimide. The inhibitor had no effect on secretion or focal adhesion formation induced by the ATP analogue, ATP gamma S in permeabilized cells, indicating ATP gamma S acts after the activation of protein kinase C in the secretory pathway. These data provide novel evidence that the formation of focal adhesions may have a role in the process of secretion from mast cells.
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PMID:Focal adhesion formation is associated with secretion of allergic mediators. 758 91


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