[45] Mast cell proteases

Woodbury, Richard G.; Everitt, Michael T.; Neurath, Hans

doi:10.1016/s0076-6879(81)80047-x

Cited by 73 publications

(29 citation statements)

References 29 publications

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“…Peritoneal mast cells, corresponding to CTMC, were isolated from male and female adult Sprague-Dawley rats (Tyler's Laboratory, Bellevue, WA) as described by Lagunoff and Pritzl (9). Typically, the entire peritoneal cell population collected from 50 rats was used to isolate mast cell granules lacking their perigranular membranes (5). For comparative purposes, granules were isolated also from highly enriched (>95%) mast cells (9).…”

Section: Methodsmentioning

confidence: 99%

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Substrate specificity of the chymotrypsin-like protease in secretory granules isolated from rat mast cells.

Trong¹,

Neurath²,

Woodbury³

1987

Proc. Natl. Acad. Sci. U.S.A.

135

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The substrate specificity of rat mast cell protease I (RMCP I), a chymotrypsin-like serine protease localized in the secretory granules of mast cells, was compared to that of bovine alpha-chymotrypsin by using several peptide and protein substrates of known amino acid sequences. Although the overall specificities of the two proteases appeared similar, subtle but significant differences were observed. RMCP I was more prone than chymotrypsin to hydrolyze peptide bonds consisting of Leu-Xaa or two hydrophobic residues--e.g., Phe-Phe. Additionally, the hydrolysis of angiotensin I catalyzed by chymotrypsin, but not by RMCP I, resulted in the generation of angiotensin II as an intermediate product. In contrast to the solubilized enzyme, the RMCP I activity within the insoluble granules was completely stable for at least 2 months in suitable buffers at pH 8.0 or pH 7.2, at 4 degrees C. Carboxypeptidase A activity associated with isolated mast cell granules was completely inhibited by 10 mM o-phenanthroline. Polypeptides smaller than apomyoglobin (17,199 Da) were rapidly hydrolyzed by granule-bound RMCP I, whereas apomyoglobin and other larger proteins were not hydrolyzed. In contrast, the free protease readily hydrolyzed the larger proteins. Neither normal rat serum nor alpha 1-antitrypsin, both of which inhibited the activity of free RMCP I, was effective in inhibiting granule-associated RMCP I. The results indicate that granule-bound RMCP I is not released into solution from isolated secretory granules under physiological conditions of ionic strength and pH and that the granule structure limits the size of proteins that can be hydrolyzed by the protease.

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Section: Methodsmentioning

confidence: 99%

“…A high proportion of the granule enzymes are serine proteases related to pancreatic chymotrypsin (3,4). Two chymotrypsin-like rat mast cell proteases have been isolated and characterized-i.e., rat mast cell protease I (RMCP I) from CTMC and rat mast cell protease II (RMCP II) from MMC (5). The functions of the proteases are not known.…”

mentioning

confidence: 99%

Substrate specificity of the chymotrypsin-like protease in secretory granules isolated from rat mast cells.

Trong¹,

Neurath²,

Woodbury³

1987

Proc. Natl. Acad. Sci. U.S.A.

135

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“…This optimum is slightly different from that for CPE (5-5.5), and much different than the neutral pH optima of other metallocarboxypeptidases (13,15,(17)(18)(19)(23)(24)(25)(26)(27). Although the pH optima of CPE and CPD are close, these two enzymes are much different at neutral pH.…”

Section: Enzymatic Properties Of Gp180mentioning

confidence: 72%

“…Other similar properties of duck gp180/ 170 and bovine CPD include the pH optima, the sensitivity to many ions, and the effect of various protease inhibitors. Some of these properties are common to all metallocarboxypeptidases, such as the inhibition by 1,10-phenanthroline, which presumably chelates the active site metal (13,15,(17)(18)(19)(23)(24)(25)(26)(27). Other properties are unique to CPD and gp180/170, such as the partial inhibition by p-chloromercuriphenyl sulfonate.…”

Section: Enzymatic Properties Of Gp180mentioning

confidence: 99%

gp180, a Protein That Binds Duck Hepatitis B Virus Particles, Has Metallocarboxypeptidase D-like Enzymatic Activity

Eng¹,

Novikova²,

Kuroki³

et al. 1998

Journal of Biological Chemistry

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Duck hepatitis B virus is a member of the hepadnavirus group, which includes human hepatitis B virus (1). These viruses are small enveloped DNA viruses that infect liver cells, causing acute and chronic hepatitis (1). The cellular receptor for human hepatitis B virus has not been identified. A candidate receptor for the duck hepatitis B virus (DHBV) 1 has recently been described (2, 3). This 180-kDa protein, named gp180, was identified based on its ability to co-precipitate with DHBV particles or recombinant DHBV envelope proteins (2). gp180 was found to bind with high affinity and specificity to the preS region of the DHBV large envelope protein (2). The binding domain within the preS region that is responsible for the gp180 interaction overlaps key areas that have been established as important for viral infectivity (4). The cDNA for gp180 has recently been cloned, revealing that gp180 is a member of the metallocarboxypeptidase gene family (3). Interestingly, gp180 contains an N-terminal signal peptide, three metallocarboxypeptidase-like domains, a putative C-terminal transmembrane domain, and a short cytoplasmic tail. Of the known carboxypeptidases, gp180 has the highest homology to carboxypeptidase E (CPE). Specifically, the first and second domains of gp180 have 39% and 43% amino acid identity with mammalian CPE, and the third domain has 29% amino acid identity.CPE functions in the biosynthesis of numerous peptide hormones and transmitters (5, 6). CPE removes C-terminal Arg and Lys residues remaining after endoprotease cleavage of the prohormone. For many years, CPE was thought to be the only carboxypeptidase involved with neuropeptide biosynthesis. However, recent studies on the Cpe fat /Cpe fat mouse suggest that additional CPE-like carboxypeptidases partially compensate for a defective CPE. These mice have a point mutation within the coding region of the CPE gene that renders the protein inactive (7). Despite the absence of active CPE in the Cpe fat /Cpe fat mice, a reduced but detectable amount of peptide processing occurs, implying that additional carboxypeptidases may perform this step in vivo. A novel carboxypeptidase with CPE-like properties, named metallocarboxypeptidase D (CPD), was identified in bovine pituitary and in other tissues (CPD) (8). In bovine tissues, the major form of CPD is 180 kDa (8). In addition to the 180-kDa form, rat tissues also contain several smaller forms ranging from 100 to 180 kDa (9). In contrast, all other known carboxypeptidases are . The size of the major species of CPD is similar to that of gp180, raising the possibility that these proteins are homologs. In addition, the partial N-terminal amino acid sequence of bovine CPD is similar to that of the duck gp180, and both proteins are

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“…Mast cells usually are present in these cases (3,4) and seem to be key players in fibrosis. Mast cells secrete a plethora of potent mediators (7)(8)(9)(10), which may be involved in the pathogenesis of fibrosis. One mast-cell product, the serine protease tryptase, is of special interest and has been shown to exert fibroproliferative action, most likely via activation of the protease-activated receptor 2 (PAR2) (1,11).…”

mentioning

confidence: 99%

Proliferative action of mast-cell tryptase is mediated by PAR2, COX2, prostaglandins, and PPARγ: Possible relevance to human fibrotic disorders

Frungieri

Weidinger

Meineke

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

238

229

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Mast-cell products can stimulate fibroblast proliferation, implying that these cells are key players in fibrosis. One mast-cell product, the serine protease tryptase, is known to activate protease-activated receptor 2 (PAR2) and cause proliferation of fibroblasts. We found that recombinant tryptase, human mastcell (HMC-1) supernatant, which contains tryptase, and the PAR2-activating peptide SLIGKV exert fibroproliferative actions in human fibroblasts. Here we report insights into this action, which after activation of PAR2 leads to increased expression of cyclooxygenase 2 (COX2), a key enzyme in the biosynthesis of prostaglandins, and consequently to enhanced prostaglandin synthesis. Subsequent cell proliferation is mediated by the prostaglandin 15-deoxy-⌬ 12,14 -prostaglandin J2, which acts via the nuclear peroxisome proliferator-activated receptor ␥ (PPAR␥). Fibroblast proliferation induced by tryptase and PAR2 agonist peptide can be blocked by antagonists of COX2 and PPAR␥, implying that the proliferative effect of tryptase is PAR2-initiated but depends on COX2, 15-deoxy-⌬ 12,14 -prostaglandin J2, and PPAR␥. This previously uncharacterized pathway could be of relevance for human fibrotic diseases. For instance, increased numbers of activated mast cells are correlated with fibrosis in testes of infertile men. In these cases all components of the signaling pathway of tryptase were detected as well as expression of COX2. Therefore, our study describes as-yet-unknown interactions between mast cells and fibroblasts, which could be relevant for human fibrotic diseases.

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[45] Mast cell proteases

Cited by 73 publications

References 29 publications

Substrate specificity of the chymotrypsin-like protease in secretory granules isolated from rat mast cells.

Substrate specificity of the chymotrypsin-like protease in secretory granules isolated from rat mast cells.

gp180, a Protein That Binds Duck Hepatitis B Virus Particles, Has Metallocarboxypeptidase D-like Enzymatic Activity

Proliferative action of mast-cell tryptase is mediated by PAR2, COX2, prostaglandins, and PPARγ: Possible relevance to human fibrotic disorders

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