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 formation of mast cell granules was studied in the beige mouse utilizing histochemistry and electron microscopy. The time and sequence of appearance of heparin, histamine and the chymotrypsin-like protease were normal. By electron microscopy, the initial formation of progranules and subsequent aggregation was normal, but the granules from early stages were abnormally large. Reorganization of intermediate granule forms to homogeneous mature granules was delayed. Late fusions of intermediate and/or mature granules were not observed. Our findings indicate that the defect lies in the excessive initial fusion of progranules rather than in continued formation of new progranules or in fusion of mature granules with one another.
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PMID:Mast cell granule formation in the beige mouse. 62 33

The protease inhibitor alpha-1-antichymotrypsin, which binds to chymotrypsin-like enzymes in a sodium dodecyl sulfate-resistant manner, has been shown recently to be both a normal constituent of brain and an integral component of the neuritic plaques that form in Down's syndrome and Alzheimer's disease. We have now identified in rat brain a Mr 25,000 alpha-1-antichymotrypsin-binding protein classified as a chymotrypsin-like protease by its inhibitor profile and substrate specificity. Release of 125I-labeled breakdown products from bands containing the protease in substrate-linked polyacrylamide gels was examined in parallel with hydrolysis of tetrapeptide chromogenic substrates in vitro to establish conditions under which the Mr 25,000 protease was the only activity being measured in vitro. The protease was completely membrane associated but was extractable using 1 M MgCl2; prior extraction of detergent- and low ionic strength-soluble proteins from membranes was used to increase its specific activity. The formation of sodium dodecyl sulfate-resistant bonds between human alpha-1-antichymotrypsin and the protease (kassoc = 2.9 X 10(6) M-1 s-1) was used to titrate the concentration of free protease solubilized from membranes. The protease cleaved both succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, and methoxy-succinyl-Ala-Ala-Pro-Met-p-nitroanilide, the latter being of interest because cleavage after a methionine residue is predicted to generate the amino terminus of the neuritic plaque component beta-amyloid from its precursor protein. In fact, the solubilized protease degraded 90% of membrane-associated beta-amyloid precursor protein detected by Western blot analysis. The protease was kinetically distinct from both chymotrypsin and cathepsin G in direct comparisons and did not match kinetic values published for the rat mast cell proteases against comparable substrates; we therefore refer to the protease with the descriptive acronym clipsin (for chymotrypsin-like protease). Proteases similar to and potentially identical to clipsin were detected by enzymography in other organs from rat (most notably spleen and adult lung). The enzyme in brain was distinguished by a narrow window of elevated activity surrounding postnatal day 5, which was 12-14-fold higher than levels in day 1 or adult brain. Because independent lines of evidence suggest that a brain chymotrypsin-like protease may be involved in the etiology of Down's syndrome and Alzheimer's disease, clipsin is discussed as a candidate for such a role.
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PMID:Clipsin, a chymotrypsin-like protease in rat brain which is irreversibly inhibited by alpha-1-antichymotrypsin. 230 81

Globule leukocytes in the epithelium of the rat trachea may be counterparts of mucosal mast cells that are located in the gastrointestinal tract. If they are indeed similar to mucosal mast cells, globule leukocytes would be expected to decrease in number in rats treated with dexamethasone but not in rats treated with compound 48/80, an agent which causes non-antigenic degranulation of connective tissue mast cells. In this study, we determined the number and compared the distribution of globule leukocytes and connective tissue mast cells in the tracheas of pathogen-free rats. We then determined whether the number of these two types of cells changes in rats treated for 5 days with compound 48/80, dexamethasone, a combination of compound 48/80 and dexamethasone, or saline. We identified globule leukocytes and mast cells in whole mounts and histological sections of rat tracheas by using a histochemical reaction that demonstrates the chymotrypsin-like protease (chloroacetate esterase) present in mast cell granules. Using this method, we found that approximately 225,000 globule leukocytes were present in the epithelium of the trachea. These cells were most abundant in the rostral trachea. Rats treated with dexamethasone had a 91% reduction in the number of globule leukocytes with protease-containing granules, but rats treated with compound 48/80 had a normal number of these cells. We found some 55,000 connective tissue mast cells in the same tracheas. Mast cells were most abundant in the posterior membrane of the caudal trachea and in the lamina propria between cartilaginous rings. Rats treated with compound 48/80 had a 96% reduction in mast cells with protease-containing granules, but rats treated with dexamethasone had a normal complement of mast cells. We conclude that globule leukocytes are abundant in the tracheas of healthy rats, are similar in morphology and pharmacological responses to mucosal mast cells located in other organs of rats, and are more numerous than and have a different distribution than connective tissue mast cells. Globule leukocytes in the tracheal epithelium may have a role in respiratory defenses similar to that of mucosal mast cells in other organs.
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PMID:Globule leukocytes and mast cells in the rat trachea: their number, distribution, and response to compound 48/80 and dexamethasone. 339 53

The isolated chymotrypsin-like protease of rat mast cells was shown to cause an increase of vascular permeability in rat skin. Inactivation of the enzymatic activity of the cationic protease abolished the vasoactivity. The smallest effective dose of the maximally active enzyme was estimated to be 0.5 micrograms per injection site, which is less than the amount of the endogenous mast cell enzyme in areas of skin similar to that of an injection site. The smallest effective dose for bovine trypsin was similarly estimated to be 0.3 micrograms per injection site, which is in good agreement with the values previously reported by others. The results suggest that the mast cell protease may act as a mediator of inflammatory vasopermeability. The effect of the enzyme on two potential biological substrates was tested. The enzyme does not hydrolyze elastin, but degrades fibrin clot.
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PMID:The role of chymotrypsin-like protease of rat mast cells in inflammatory vasopermeability and fibrinolysis. 699 62

Cleavage after Met596 of the beta-amyloid precursor protein to generate the N-terminus of beta-protein indicates the activity of a protease having chymotrypsin-like specificity. A chymotrypsin-like protease is further implicated in Alzheimer's disease by the increased synthesis of the protease inhibitor alpha 1-antichymotrypsin in pathologically affected brain regions and by the presence in the amyloid deposits of inactivated forms of alpha 1-antichymotrypsin (indicating irreversible binding to a target chymotrypsin-like protease). In the present report, we have purified from rat brain a chymotrypsin-like protease that (a) binds with high affinity to human alpha 1-antichymotrypsin, (b) proteolytically generates a beta-protein-containing C-terminal fragment from full-length recombinant human beta-amyloid precursor protein, and (c) selectively cleaves methoxysucinyl-Glu-Val-Lys-Met- p-nitroanilide (a substrate modeling the protease recognition domain for the beta-protein N-terminal cleavage site). Amino acid sequences of tryptic fragments of the purified rat brain chymotrypsin-like protease indicate an identity with rat mast cell protease I. Moreover, the ontogeny and compartmentalization of rat brain chymotrypsin-like protease are consistent with those of connective tissue-type mast cells in the meningeal and intracortical perivasculature. Because these areas in human brain form extensive beta-amyloid deposits in Alzheimer's disease, Down's syndrome, and hereditary cerebral hemorrhage with amyloidosis of Dutch origin, the present findings suggest that a brain mast cell chymotrypsin-like protease may participate in generating perivascular beta-protein, which ultimately aggregates into beta-amyloid deposits.
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PMID:Identification of a chymotrypsin-like mast cell protease in rat brain capable of generating the N-terminus of the Alzheimer amyloid beta-protein. 833 43

Stem cell factor (SCF) is produced by stromal cells as a membrane-bound molecule, which may be proteolytically cleaved at a site close to the membrane to produce a soluble bioactive form. The proteases producing this cleavage are unknown. In this study, we demonstrate that human mast cell chymase, a chymotrypsin-like protease, cleaves SCF at a novel site. Cleavage is at the peptide bond between Phe-158 and Met-159, which are encoded by exon 6 of the SCF gene. This cleavage results in a soluble bioactive product that is 7 amino acids shorter at the C terminus than previously identified soluble SCF. This research shows the identification of a physiologically relevant enzyme that specifically cleaves SCF. Because mast cells express the KIT protein, the receptor for SCF, and respond to SCF by proliferation and degranulation, this observation identifies a possible feedback loop in which chymase released from mast cell secretory granules may solubilize SCF bound to the membrane of surrounding stromal cells. The liberated soluble SCF may in turn stimulate mast cell proliferation and differentiated functions; this loop could contribute to abnormal accumulations of mast cells in the skin and hyperpigmentation at sites of chronic cutaneous inflammation.
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PMID:Chymase cleavage of stem cell factor yields a bioactive, soluble product. 925 27

To gain insight into the biological role of mast cell chymase we have generated a mouse strain with a targeted deletion in the gene for mast cell protease 4 (mMCP-4), the mouse chymase that has the closest relationship to the human chymase in terms of tissue localization and functional properties. The inactivation of mMCP-4 did not affect the storage of other mast cell proteases and did not affect the number of mast cells or the mast cell morphology. However, mMCP-4 inactivation resulted in complete loss of chymotryptic activity in the peritoneum and in ear tissue, indicating that mMCP-4 is the main source of stored chymotrypsin-like protease activity at these sites. The mMCP-4 null cells showed markedly impaired ability to perform inactivating cleavages of thrombin, indicating a role for mMCP-4 in regulating the extravascular coagulation system. Further, a role for mMCP-4 in connective tissue remodeling was suggested by the inability of mMCP-4 null peritoneal cells to process endogenous fibronectin.
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PMID:The chymase, mouse mast cell protease 4, constitutes the major chymotrypsin-like activity in peritoneum and ear tissue. A role for mouse mast cell protease 4 in thrombin regulation and fibronectin turnover. 1290 May 18