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)

A novel plasminogen-binding protein has been isolated from human plasma utilizing plasminogen-Sepharose affinity chromatography. This protein copurified with alpha 2 antiplasmin when the plasminogen affinity column was eluted with high concentrations of epsilon-aminocaproic acid (greater than 20 mM). Analysis by sodium dodecyl sulfate suggests this protein has an apparent Mr of 60,000. The amino-terminal amino acid sequence showed no similarity to other protein sequences. Based on the amino-terminal amino acid sequence, oligonucleotide probes were designed for polymerase chain reaction primers, and an approximately 1,800 base pair cDNA was isolated that encodes this Mr 60,000 protein. The deduced amino acid sequence reveals a primary translation product of 423 amino acids that is very similar to carboxypeptidase A and B and consists of a 22-amino acid signal peptide, a 92-amino acid activation peptide, and a 309-amino acid catalytic domain. This protein shows 44 and 40% similarity to rat procarboxypeptidase B and human mast cell procarboxypeptidase A, respectively. The residues critical for catalysis and zinc and substrate binding of carboxypeptidase A and B are conserved in the Mr 60,000 plasminogen-binding protein. The presence of aspartic acid at position 257 of the catalytic domain suggests that this protein is a basic carboxypeptidase. When activated by trypsin, it hydrolyzes carboxypeptidase B substrates, hippuryl-Arg and hippuryl-Lys, but not carboxypeptidase A substrates, and it is inhibited by the specific carboxypeptidase B inhibitor (DL-5-guanidinoethyl)mercaptosuccinic acid. We propose that the Mr 60,000 plasminogen-binding protein isolated here is a novel human plasma carboxypeptidase B and that it be designated pCPB.
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PMID:Isolation, molecular cloning, and partial characterization of a novel carboxypeptidase B from human plasma. 193 7

The normal balance between coagulation and fibrinolysis in the pleural cavity is poorly understood despite the critical role of the pleura in the movement of the lungs. To determine the fibrinolytic activity and the interaction between plasminogen activators and their inhibitors in the normal pleural space, we tested normal rat pleural leukocytes, principally macrophages and mast cells, and their supernatants, for activity in an [125I]fibrin degradation assay. It was found that pleural leukocytes did not release plasminogen activator, but the leukocytes and their supernatants inhibited the plasminogen-dependent fibrinolysis caused by both alveolar leukocytes and mesothelial cells. Further experiments demonstrated that pleural leukocytes produce a protein inhibitor primarily against urokinase-induced fibrinolysis in culture and that macrophages are the main source of the inhibitor. The lysate of mast cell-enriched population exhibited high plasminogen activator activity while no such activity could be determined in macrophage-enriched lysate. These data show that normal rat pleural leukocytes contain plasminogen activator inside the cells and synthesize a urokinase-type plasminogen activator inhibitor in culture that may be important in the fibrinolysis/coagulation balance in the pleural space.
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PMID:Secretion of plasminogen activator inhibitor by normal rat pleural leukocytes in culture. 212 20

Mast cells from the Furth murine mastocytoma tumour line were found to contain significant levels of plasminogen activator (PA). Cultured cells released PA activity into the culture medium in parallel with the release of histamine, and both were proportionately increased following exposure to degranulating agents. Pretreatment of the mast cells with cycloheximide did not alter their total PA content or their ability to release PA. These studies suggest that PA is a prestored granule constituent. The ability of PA to generate plasmin from plasminogen suggests an important role for mast cell PA in fibrinolysis and tissue degradation, observations that have been associated with mast cell degranulation and infiltration in vivo.
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PMID:Plasminogen activator release from cultured murine mast cells. 313 12

The capacity of purified tryptase from human lung mast cells to metabolize human fibrinogen, fibrin, and plasminogen was evaluated. Tryptase (5 micrograms/ml) inactivated the thrombin-induced clotting activity of fibrinogen (100 micrograms/ml) with essentially similar t 1/2 values of 4.6 min in the absence of heparin and 5.8 min in the presence of heparin (20 micrograms/ml) that were not appreciably different than with lysine-Sepharose-purified plasmin (5 micrograms/ml). Fibrinogen treated with tryptase together with heparin lost all detectable clotting activity by 4 hr at 37 degrees C, whereas fibrinogen treated with tryptase alone resulted in destruction of only 80% of fibrinogen clotting equivalents after 16 hr. Tryptase alone was observed to cleave only the alpha-chains of fibrinogen by electrophoresis of tryptase-treated, denatured, and reduced fibrinogen in polyacrylamide gradient gels. Tryptase together with heparin cleaved first the alpha-chain and then the beta-chain, the latter cleavage corresponding to complete loss of fibrinogen clotting activity by 4 hr. No fibrinogen fragments with anticoagulant activity were generated by tryptase. In contrast, plasmin left no residual clotting activity after 4 hr of incubation and generated fibrinogen fragments with anticoagulant activity. Plasmin sequentially cleaved the alpha, beta, and gamma subunits of fibrinogen. Tryptase alone (6 micrograms/ml) or together with heparin (20 micrograms/ml) failed to activate plasminogen (0.6 mg/ml) after a 60-min incubation at 37 degrees C. Addition of urokinase to tryptase-treated or untreated plasminogen resulted in essentially identical plasmin activities (0.32 and 0.34 U/ml, respectively), indicating that tryptase neither activates nor destroys plasminogen. Tryptase (700 ng) also failed to substantially solubilize cross-linked fibrin (2.6 micrograms) or the corresponding amount of fibrinogen bound to plastic microtiter plates with or without heparin. The failure to solubilize fibrinogen and, possibly, fibrin is consistent with the observation that the apparent m.w. by SDS polyacrylamide gel electrophoresis of unreduced fibrinogen is not appreciably altered by prior treatment with tryptase, even though cleavage of alpha-and beta-chains is revealed after reduction. Fibrinogenolysis by tryptase complements other mast cell mediators with anticoagulant properties such as heparin and suggests a significant prevention of coagulation by activated mast cells.
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PMID:The fibrinogenolytic activity of purified tryptase from human lung mast cells. 316 48

The complete sequence of 157 amino acids of the light (A) chain of high molecular mass urokinase from human urine was determined. The fragmentation strategy included cyanogen bromide cleavage of the S-carboxymethylated A chain at the methionine and/or tryptophan residues and use of the specific endoproteinase Lys-C. For sequence determination automated solid- or liquid-phase techniques of Edman degradation were used. C-terminal amino acids of the A chain were determined by consecutive treatment with carboxypeptidase A and B. The amino acid sequence obtained revealed a significant homology to peptide chains of other serine proteinases. Accordingly, the sequence of the A chain can be divided into three domains: 1) The growth factor domain with homologies to murine epidermal growth factor and a particular sequence of bovine clotting factor X, 2) The "kringle" domain with homologies to "kringle" structures, e.g. in plasminogen, and 3) the connecting peptide domain containing the A1 chain of low molecular mass urokinase. Together with the amino acid sequence of the B chain, which was presented by us in an earlier communication, the sequence data presented complete the primary structure of high molecular mass urokinase from human urine.
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PMID:The primary structure of high molecular mass urokinase from human urine. The complete amino acid sequence of the A chain. 675 69

The pathogenesis of anaphylactic shock is not completely understood. Mast cell degranulation products may stimulate endothelial cells, leading to activation of fibrinolytic and coagulation systems. We investigated the activation of these systems in insect-sting anaphylaxis. Fifty-five patients with a previous insect-sting anaphylactic reaction and 8 volunteers were challenged with an in-hospital sting. Plasma levels of von Willebrand factor (vWF), coagulation, and fibrinolytic parameters were assessed. After the sting challenge, 20 patients developed anaphylactic symptoms, 7 of whom developed hypotension. In only these 7 patients, but not in the volunteers or in the other patients with no or mild anaphylactic symptoms, vWF levels increased from 107% +/- 33% (mean +/- SD) before, to 235% +/- 134% 60 minutes after the onset of clinical symptoms. This increase of vWF was accompanied by an increase of circulating tissue-type plasminogen-activator (tPA) levels from 5 +/- 3 micrograms/L to 50 +/- 59 micrograms/L and of plasminogen-alpha 2-antiplasmin complex (PAP-c) levels from 6 +/- 3 nmol/L to 297 +/- 225 nmol/L. Both tPA and PAP-c levels peaked 5 minutes after the onset of clinical symptoms. Such increases of tPA and PAP-c were not observed in the volunteers or in the patients who did not develop shock. The increase of tPA and PAP-c levels in the hypotensive patients correlated positively with the degree of mast cell degranulation and inversely with the mean arterial pressure. We conclude that activation of plasminogen may be involved in the pathogenesis of anaphylactic shock induced by insect venom.
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PMID:Controlled insect-sting challenge in 55 patients: correlation between activation of plasminogen and the development of anaphylactic shock. 769 Dec 34

It is no surprise to anyone who has tried to memorize clotting and complement cascades that there are a great many trypsin-like proteases-too many, it may seem. This fecund enzyme family encompasses such a range of biological roles that other important members and functions are sure to await discovery. Of known trypsin-like proteases, few, if any, are lung-specific. Nonetheless, many contribute in ways critical to lung function, such as fighting microbial invaders, regulating the formation and removal of polymerized fibrin, and rejecting tumors or transplanted tissues. Some of these enzymes, such as plasminogen activators and mast cell tryptases, are native to the lung and live where they work; identical enzymes live and work in other tissues. Other enzymes, such as most complement and hemostatic proteases, are migrants, typically born elsewhere (e.g., the liver). They pass through the lung, looking for something to do; if nothing is found, they pass on, circulating, perhaps to return later. Still others are unwanted, uninvited intruders, such as dust mite proteases. This minireview provides a selective glimpse of the lives of some of the trypsin-like enzymes at work in the lung and airways.
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PMID:Of mites and men: trypsin-like proteases in the lungs. 919 63

Thrombin-activable fibrinolysis inhibitor (TAFI) is a recently described human plasma zymogen that is related to pancreatic carboxypeptidase B. The active form of TAFI (TAFIa), which is formed by thrombin cleavage of the zymogen, likely inhibits fibrinolysis by removal from partially degraded fibrin of the carboxyl-terminal lysine residues which act to stimulate plasminogen activation. We have isolated and characterized genomic clones which encompass the entire human TAFI gene from lambda phage and bacterial artificial chromosome genomic libraries. The complete TAFI gene contains 11 exons and spans approximately 48 kb of genomic DNA. The positions of intron/exon boundaries are conserved between the TAFI gene and the rat pancreatic carboxypeptidase A1, A2, and B and the human mast cell carboxypeptidase A genes, indicating that these carboxypeptidases arose from a common ancestral gene. However, the intron lengths diverge significantly among all of these genes. The TAFI promoter lacks a consensus TATA sequence, and transcription is initiated from multiple sites. Transient transfection of reporter plasmids containing portions of the TAFI 5'-flanking region into mammalian cells allowed localization of the promoter and identified a approximately 70 bp region crucial for liver-specific transcription. Sequence analysis of cDNA clones obtained from human liver RNA indicated that the TAFI transcript is polyadenylated at three different sites. Our findings will facilitate the assessment of the regulation of TAFI expression by transcriptional and/or posttranscriptional mechanisms. Furthermore, knowledge of the genomic structure of the TAFI gene will aid in the identification of mutations that may be associated with the tendency to either bleed or thrombose.
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PMID:Characterization of the gene encoding human TAFI (thrombin-activable fibrinolysis inhibitor; plasma procarboxypeptidase B). 1035 Apr 73

Lung cancer is one of the commonest causes of cancer death in developed countries. Recent evidence suggests that angoigenesis is related to poor prognosis in many solid tumors including non-small cell lung cancer (NSCLC). Angiogenesis is regulated by a complex interaction among growth factors and cytokines and influenced by proteolytic enzymes such as plasminogen activators and matrix metalloproteases, expression of adhesion molecules, and distribution of extracellular matrices. Fibroblasts, macrophages, mast cells, and endothelial cells themselves also affect angiogenesis. This review concentrates on angiogenic growth factors including vascular endothelial growth factor, angiopoietins, platelet derived endothelial growth factor, and basic fibroblast growth factor, proteases, adhesion molecules including vascular endothelial cadherin and integrins, osteopontin, and mast cell products in tumor angiogenesis of NSCLC.
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PMID:Tumor angiogenesis of non-small cell lung cancer. 1253 73

We report on a patient with coagulation abnormalities induced by a wasp sting anaphylaxis. First, we observed an unclottable activated partial thromboplastin time and a significant anti-Xa activity (equivalent to a therapeutic heparin range), whereas the patient had received no heparin. This phenomenon is probably due to activated mast cells that release mediators such as heparin and tryptase. Heparin can then act as an anticoagulant by binding to antithrombin. This "heparinization" explains the anti-Xa activity contributing to the unclottable activated partial thromboplastin time detected in our patient. Second, we noted an extremely low fibrinogen level in the presence of normal platelet count and only a slight increase of D-dimers (absence of important disseminated intravascular coagulation). This is probably due to serum tryptase released during massive mast cell activation. Tryptase cleaves the alpha and beta chains of fibrinogen. This results in the removal of the thrombin cleavage site and of the critical polymerization site from the fibrinogen beta chain. Thrombin- initiated clot formation is therefore inhibited. Tryptase also acts directly on the fibrinolytic pathway by activating the single-chain urinary-type plasminogen activator, resulting in conversion of plasminogen into plasmin and therefore degradation of fibrinogen and other coagulation factors. This hyperfibrinogenolysis explains both the prolonged clotting times and the low fibrinogen level observed. Although our patient did not bleed, in other settings (trauma, during surgery) patients with anaphylaxis may present bleeding disorders. Although the mechanisms underlying these abnormalities have been described in vitro and in vivo animal trials, this is the first time they are described in a human clinical setting.
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PMID:"Heparinization" and hyperfibrinogenolysis by wasp sting. 2207 26


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