Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The correlation between malignant transformation and increased PA synthesis or secretion has been examined in a variety of cell lines. To study the relationship between content and composition of PAs and colorectal neoplasms, we measured u-PA and t-PA antigen levels in normal mucosa, tubular adenoma, adenocarcinoma in adenoma, and adenocarcinoma, using a sensitive sandwich enzyme immunoassay. This assay was very sensitive and was not hindered by the presence of serine protease inhibitors. Both adenomas and carcinomas had higher u-PA antigen levels than normal mucosa. The u-PA antigen level of adenomas was lower than that of carcinomas. Antigen level of t-PA, however, was lower in both adenomas and carcinomas compared with that in normal mucosa, the values being lowest in carcinomas. Two cases of carcinoma in adenoma had PA contents similar to those of carcinomas. u-PA antigen level of adenomas with dysplastic epithelium was higher than that of adenomas without dysplastic epithelium. Therefore, the increase of u-PA content in adenomas could be a parameter of malignant changes in adenomas.
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PMID:Comparative study of plasminogen activator antigens in colonic carcinomas and adenomas. 317 33

Apolipoprotein(a) [apo(a)] is a glycoprotein with Mr approximately equal to 280,000 that is disulfide linked to apolipoprotein B in lipoprotein(a) particles. Elevated plasma levels of lipoprotein(a) are correlated with atherosclerosis. Partial amino acid sequence of apo(a) shows that it has striking homology to plasminogen. Plasminogen is a plasma serine protease zymogen that consists of five homologous and tandemly repeated domains called kringles and a trypsin-like protease domain. The amino-terminal sequence obtained for apo(a) is homologous to the beginning of kringle 4 but not the amino terminus of plasminogen. Apo(a) was subjected to limited proteolysis by trypsin or V8 protease, and fragments generated were isolated and sequenced. Sequences obtained from several of these fragments are highly (77-100%) homologous to plasminogen residues 391-421, which reside within kringle 4. Analysis of these internal apo(a) sequences revealed that apo(a) may contain at least two kringle 4-like domains. A sequence obtained from another tryptic fragment also shows homology to the end of kringle 4 and the beginning of kringle 5. Sequence data obtained from two tryptic fragments show homology with the protease domain of plasminogen. One of these sequences is homologous to the sequences surrounding the activation site of plasminogen. Plasminogen is activated by the cleavage of a specific arginine residue by urokinase and tissue plasminogen activator; however, the corresponding site in apo(a) is a serine that would not be cleaved by tissue plasminogen activator or urokinase. Using a plasmin-specific assay, no proteolytic activity could be demonstrated for lipoprotein(a) particles. These results suggest that apo(a) contains kringle-like domains and an inactive protease domain.
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PMID:Partial amino acid sequence of apolipoprotein(a) shows that it is homologous to plasminogen. 347 6

The effects of insulin, the tumour promotor tetradecanoyl phorbol acetate (TPA), TSH and combinations of these factors on growth and DNA synthesis have been examined in the FRTL-5 cell strain and in sheep thyroid cells. In addition the regulation of the production by sheep thyroid cells of the insulin-like growth factors (IGF) by TSH and their possible autocrine roles have been investigated. We found that insulin and the IGF's stimulated DNA synthesis in both rat FRTL-5 cells and sheep cells. TPA also stimulated growth in both cell types, and its effects were additive to those of insulin. In the FRTL-5 cells, TPA was a less potent stimulator of growth than TSH, but the effects of TPA and TSH were not additive which may imply growth stimulation through a common pathway. In sheep cells TSH was not mitogenic and did not appear to activate protein kinase C, the receptor for TPA. Sheep cells, unlike FRTL-5 cells, were found to produce IGF-I and IGF-II, and their syntheses were regulated by TSH. Sheep cells were also found to produce IGF-binding proteins which may modulate the biologic effects of the IGF's. Sheep thyroid IGF binding proteins were found to copurify with urokinase-like plasminogen activator on immunoaffinity chromatography. The production of this serine protease has also been shown to be regulated by TSH.
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PMID:Role of non-TSH factors in thyroid cell growth. 347 6

The kinetics of the activation of Glu- and Lys-plasminogen by single-chain urokinase (sc urokinase) derived from the transformed human kidney cell line TCL-598 have been studied and compared with two-chain urokinase (tc urokinase). Plasminogen activation was determined by the increase in fluorescence polarization of fluorescein-labeled aprotinin, a high affinity inhibitor of plasmin. This methodology allows plasmin generation by sc urokinase to be measured in functional isolation, with no interfering generation of tc urokinase, sc urokinase was found to activate plasminogen to plasmin with apparent Michaelis-Menten-type kinetics. The Km for Glu-plasminogen activation was 47.7 microM, with a catalytic constant of 2.91 min-1. Lys-plasminogen activation by sc urokinase was characterized by a Km of 11.7 microM and a kcat of 5.60 min-1. The Km values for the activation of Glu- and Lys-plasminogen by tc urokinase were found to be similar to those for activation by sc urokinase (36.8 and 9.0 microM, respectively), but the catalytic constants were higher at 36.0 and 118 min-1, respectively. Therefore, on the basis of the catalytic efficiency kcat/Km, sc urokinase seems to have 16-27-fold lower activity than tc urokinase. This activity of sc urokinase is in contrast to its lack of activity against a low molecular weight peptide substrate (less than 0.2% of the activity of sc urokinase). The activation of sc urokinase to tc urokinase by plasmin was also characterized (Km = 3.0 microM, kcat = 105 min-1). Using these data, it was possible to calculate the theoretical rate of plasminogen activation by sc urokinase in the absence of aprotinin, when tc urokinase is generated by the action of plasmin. The calculated rate was in good agreement with that determined experimentally using the chromogenic substrate D-Val-Leu-Lys-p-nitroanilide. These data demonstrate that sc urokinase has properties which distinguish it from conventional serine protease zymogens. The lack of activity against low molecular weight peptide substrates demonstrates the inaccessibility of the substrate-binding pocket. However, there is a moderate activity against plasminogen, suggesting that plasminogen may be acting as both an effector and a substrate for sc urokinase.
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PMID:Plasminogen activation by single-chain urokinase in functional isolation. A kinetic study. 366 21

Protease nexin-I (PN-I) is representative of a newly described class of serine protease inhibitors secreted by human fibroblasts, the protease nexins. Protease nexins form covalent complexes with their target proteases, subsequently binding to cells via specific receptors. PN-I preferentially binds thrombin, urokinase, trypsin, and plasmin, and its binding to thrombin is accelerated by heparin. We have previously described the production of a polyclonal antibody against PN-I which is able to block the binding of PN-I X proteinase complexes to cells and will immunoprecipitate metabolically labeled PN-I. Anti-PN-I was used to investigate the biosynthesis and regulation of PN-I in human fibroblasts. Unlabeled PN-I could compete for the binding of metabolically labeled PN-I to anti-PN-I, as shown by the elimination of the 43-kDa band representing PN-I on sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiographs. Excision of this 43-kDa band from gels, followed by amino-terminal sequencing, showed a homogeneous protein that is homologous with that described by Scott et al. (Scott, R. W., Bergman, B. L., Bajpai, A., Hersh, R. T., Rodriguez, H., Jones, B. N., Barreda, C., Watts, S., and Baker, J. B. (1985) J. Biol. Chem. 260, 7029-7034). An analysis of the biosynthesis of the PN-I revealed that a lower Mr precursor exists intracellularly. This apparent rough endoplasmic reticulum form appears as a doublet on sodium dodecyl sulfate gels, as does mature PN-I. The PN-I precursor was also sensitive to endoglycosidase H, suggesting that it contains N-linked carbohydrates of the high mannose form. Mature PN-I is not sensitive to endoglycosidase H, but does contain 3 kDa of N-linked carbohydrate. PN-I appears to be constitutively secreted by fibroblasts. PN-I levels in conditioned media reach a steady state within 48 h, although PN-I synthesis maintains a constant rate. This steady state is due to the continuous uptake of PN-I from medium, presumably through a specific receptor.
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PMID:Biosynthesis of protease nexin-I. 377 29

Ancrod is a thrombinlike enzyme from Malayan pit viper (Agkistrodon rhodostoma) venom that has a selective enzyme substrate specificity for fibrinogen. Unlike thrombin, it splits only fibrinopeptide A from the fibrinogen molecule and does not activate factor XIII. Simultaneously with the occurrence of hypofibrinogenemia there is a reduction of plasma plasminogen and a rise in fibrin degradation products, suggesting secondary recruitment of the fibrinolytic enzyme system. Ancrod was given to 18 patients with systemic lupus erythematosus and glomerular and vascular microthrombi. Before treatment vascular plasminogen activator (VPA) was low or unmeasurable in 14, an inhibitor of urokinase-induced plasminogen activation (IPA) was elevated in 18, and an inhibitor of plasmin (PI) was elevated in five. Ancrod treatment resulted in prompt normalization of IPA levels in 13 patients; they were classified as fibrinolysis responders. In five patients IPA levels remained elevated throughout treatment with ancrod; they were classified as fibrinolysis nonresponders. In these five the PI level was elevated before treatment and decreased slowly toward the normal range during ancrod administration. The PI did not appear related to the nonspecific serine protease inhibitors, and was shown to be identical with alpha 2-antiplasmin. In the fibrinolysis responders serial histologic studies showed a striking decrease of disappearance of microvascular thrombosis; in the fibrinolysis nonresponders microvascular thrombosis persisted. The action of ancrod is discussed.
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PMID:Ancrod: normalization of fibrinolytic enzyme abnormalities in patients with systemic lupus erythematosus and lupus nephritis. 387 65

Since serine protease in involved in histamine release from mast cells, we attempted to prepare new protease inhibitors, trans-4-(guanidinomethyl)cyclohexanecarboxylic acid (GmcHX-CO2H) esters, and examined their inhibitory effects on typical serine proteases and on histamine release induced by compound 48/80. We compared their effects with those of trans-4-(aminomethyl)cyclohexanecarboxylic acid (AmcHx-CO2H) esters. AmcHxCO2H and GmcHxCO2H esters inhibited the esterolytic activity of trypsin, but GmcHx-CO2H esters had little or no inhibitory effect on caseinolytic activity whereas AmcHxCO2H esters strongly inhibited the latter. AmcHCO2H esters strongly inhibited plasmin but had no effect on chymotrypsin. GmcHxCO2H esters strongly inhibited the esterolytic activity of chymotrypsin, but had no effect on chymotrypsin-induced caseinolysis. Both GmcHxCO2H an AmcHxCO2H esters inhibited urokinase. Of the esters of AmcHxCO2H and GmcHxCO2H tested, only GmcHxCO2H p-tert-butylphenyl ester (GmcHxCOOPhBut) at low concentration (27 microM) strongly inhibited histamine release from rat mast cells induced by compound 48/80. GmcHxCOOPhBut was effective in preventing active systemic anaphylaxis and passively sensitized guinea pigs. Its effectiveness in preventing anaphylactic phenomena might be due to its strong inhibitory effects on histamine release from mast cells.
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PMID:Inhibitory effects of aryl trans-4-(aminomethyl)cyclohexanecarboxylate and aryl trans-4-(guanidinomethyl)cyclohexanecarboxylate on serine proteases, and their antiallergic effects. 617 16

Cultured bovine capillary endothelial (BCE) cells produce low levels of collagenolytic activity and significant amounts of the serine protease plasminogen activator (PA). When grown in the presence of nanomolar quantities of the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA), BCE cells produced 5-15 times more collagenolytic activity and 2-10 times more PA than untreated cells. The enhanced production of these enzymes was dependent on the dose of TPA used, with maximal response at 10(-7) to 10(-8) M. Phorbol didecanoate (PDD), an analog of TPA which is an active tumor promoter, also increased protease production. 4-O-methyl-TPA and 4alpha-PDD, two analogs of TPA which are inactive as tumor promoters, had no effect on protease production. Increased PA and collagenase activities were detected within 7.5 and 19 h, respectively, after the addition of TPA. The TPA-stimulated BCE cells synthesized a urokinase-type PA and a typical vertebrate collagenase. BCE cells were compared with bovine aortic endothelial (BAE) cells and bovine embryonic skin (BES) fibroblasts with respect to their production of protease in response to TPA. Under normal growth conditions, low levels of collagenolyic activity were detected in the culture fluids from BCE, BAE, and BES cells. BCE cells produced 5-13 times the basal levels of collagenolytic activity in response to TPA, whereas BAE cells and BES fibroblasts showed a minimal response to TPA. Both BCE and BAE cells exhibited relatively high basal levels of PA, the production of which was stimulated approximately threefold by the addition of TPA. The observation that BCE cells and not BAE cells produced high levels of both PA and collagenase activities in response to TPA demonstrates a significant difference between these two types of endothelial cells and suggests that the enhanced detectable activities are a property unique to bovine capillary and microvessel and endothelial cells.
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PMID:Plasminogen activator and collagenase production by cultured capillary endothelial cells. 618 6

Methods are described to measure fibrinolysis in healthy persons and in patients with systemic lupus erythematosus. Using the fibrin plate method, total fibrinolytic activity and vascular plasminogen activator were measured. (Total fibrinolytic activity expresses the fibrinolytic potential and consists of both the intrinsic [factor XII-dependent and independent] activities and the extrinsic activities [vascular or tissue type]. Vascular plasminogen activator, assessed in a separate assay, refers to the endothelium-derived component only.) In addition, the degree of inhibition by plasma of both urokinase-induced and of plasmin-induced fibrinolysis were analyzed. Vascular plasminogen activator levels were low in 63% of plasma samples from 55 patients with systemic lupus erythematosus. The level of an inhibitor of plasminogen activation was significantly elevated in 87% of patients and levels of an inhibitor of plasmin were significantly elevated in 29%. The nonspecific serine protease inhibitors, including alpha 2-macroglobulin, were within the normal range in all patients. The natures of inhibitor of plasminogen activation and plasmin inhibitor were studied further. Using both the fibrin plate and the lysis time methods, the data indicated that the urokinase-inhibiting activity increased with time of incubation of plasma-enzyme mixtures, whereas the plasmin inhibiting activity did not. Elevated levels of plasmin inhibitor measured with the fibrin plate method correlated well with prolonged lysis times. Results using the chromogenic substrate S-2251, commonly used as a simple and specific assay for antiplasmin, agreed reasonably well with those using the fibrin plate method, but elevated plasmin inhibitor levels could be quantitated with greater accuracy and sensitivity by the fibrin plate method. Studies with an antiserum directed against alpha 2-antiplasmin showed that inhibitor of plasminogen activation and plasmin inhibitor were different inhibitors, and that plasmin inhibitor was identical to alpha 2-antiplasmin. The abnormalities are discussed in the light of current knowledge on fibrinolysis and as possible mediators in the pathogenesis and perpetuation of lupus glomerulonephritis.
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PMID:Fibrinolysis in health and disease: severe abnormalities in systemic lupus erythematosus. 623

We have reported previously that derivatives of adenosine cyclic 3':5'-monophosphate dramatically stimulate the activity of plasminogen activator (PA), an arginine-specific serine protease, in HTC rat hepatoma cells. We report here that these derivatives also cause striking alterations in hepatoma tissue culture cell morphology. Because PA has been shown to alter cell morphology in other cell lines, we investigated whether the morphological changes induced by cyclic nucleotides were mediated by the stimulation of PA activity. Alterations in PA activity, measured by the plasminogen-dependent solubilization of 125I-labeled fibrin, and in cell morphology, detected by evaluation of cell flattening and process extension with phase-contrast microscopy, were assessed in the same cultures under various experimental conditions. Several lines of evidence clearly dissociate these two adenosine cyclic 3':5'-monophosphate-mediated phenomena. (a) The morphological changes precede increases in either cell-associated or extracellular PA activity. (b) Upon removal of the effectors, the morphological effects are completely reversed at a time when PA activity is still considerably elevated. (c) when protein synthesis is inhibited by the addition of cycloheximide, the stimulation of PA activity by cyclic nucleotides is blocked completely, whereas the induction of morphological alterations still occurs. (d) An exogenous PA, urokinase, does not elicit the characteristic changes in cell shape. We conclude that the morphological alterations induced by adenosine cyclic 3':5'-monophosphate derivatives in HTC cells are not mediated by the stimulation of PA activity and that these two membrane-associated properties are regulated independently.
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PMID:Role of plasminogen activator in the morphological alterations induced by derivatives of adenosine cyclic 3':5'-monophosphate in hepatoma tissue culture cells. 631 21


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