Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The goal of the present study was to assess the relative importance of receptor-bound and secreted plasminogen activator urokinase (u-PA) in generating cell-surface plasmin and fostering destruction of normal tissue by tumor cells. We first showed that active site-inhibited u-PA could displace endogenous u-PA from the surface of the human colon adenocarcinoma cell line HCT 116. We then prepared expression vectors for u-PA and for a mutant molecule in which the codon for the active site serine residue was changed to encode alanine. Expression of non-functional mutant u-PA decreased the level of cell-bound active u-PA by more than 95% via a mechanism that involved competition for receptor sites. Decreased cell-surface u-PA activity was associated with a decrease in cell-bound plasmin activity to undetectable levels, suggesting that receptor-bound u-PA plays an important role in the generation of plasmin on the cell surface. Transfectants that secreted eightfold to 20-fold elevated levels of active wild-type u-PA showed approximately 50% increases in cell-associated u-PA and only twofold to fourfold increases in cell-associated plasmin, suggesting that the role of secreted u-PA in generating cell-surface plasmin activity was relatively minor. In parent cells and both types of transfectants there was a good correlation between the amount of plasmin bound to the tumor cell surface and the extent to which a basement membrane substrate was degraded. These studies show that receptor-bound u-PA provides an efficient mechanism for plasmin generation on the surface of tumor cells, which, in turn, contributes significantly to their degradative potential.
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PMID:Effects of urokinase receptor occupancy on plasmin generation and proteolysis of basement membrane by human tumor cells. 164 83

In a previous study of plasma specimens from reactors to clinical dextran, it was concluded that a factor activated by acetone converted the high-molecular-weight kininogen (HMrK) into a non-functional state. We recently identified the HMrK-destroying factor as a plasma kallikrein modification with high plasminogen activator (PGA) activity. The aim of the present work was to investigate whether the level of plasma kallikrein, assayed as PGA on fibrin plates, was higher than normal in plasma from patients reacting to dextran or radiographic contrast media. Plasma specimens from 10 reactors and 16 controls were examined. No difference in PGA level could be detected between reactors and controls in citrated plasma stabilized with benzamidine 9 mM, whereas a significant loss of PGA activity took place in citrated reactor plasma during the acetone activation procedure. The loss of PGA activity could not be due to known inhibitors of plasma kallikrein. It was only partial, and did not influence the amidase effect against the tripeptide substrate H-D-Pro-Phe-Arg-pNA. The results might indicate the presence in plasma of different amounts of an unknown constituent important for the obtainable level of plasma kallikrein with high PGA activity. The significant loss of PGA activity in reactor plasma might indicate an abnormally high level of the unknown plasma factor.
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PMID:Assay of prekallikrein as plasminogen proactivator in plasma specimens from reactors to dextran or to contrast media. 608 73

Induction of an immune response is strongly dependent on the phylogenetic distance between antigen and recipient. In general, antibodies will not be raised against self-antigens nor against highly conserved domains. In the present study we describe the production and characterization of murine monoclonal "auto-antibodies" against murine tissue-type plasminogen activator (t-PA) raised in "knock-out" mice, homozygously deficient of the functional gene. 203 stable hybridomas were obtained producing murine monoclonal antibodies against murine t-PA. Analysis of the species reactivity revealed that 182 cross-reacted with one or more (t-)PAs originating from other species including rat t-PA, human t-PA, and vampire bat-PA. 121 reacted with epitopes conserved among murine, rat, and human t-PA. In addition, 31 of the monoclonal antibodies were directed against domains present in all four species. Epitope mapping indicated a high frequency of specificity toward diverse epitopes that are highly conserved across species. Comparative analysis of their influence on the enzymatic activity of t-PA and their species cross-reactivity clearly demonstrated that the domains required for the biological activity of plasminogen activators are more conserved (p < 0.02) than non-functional domains. The availability of such unique antibodies against a wide variety of conserved epitopes may facilitate studies on the structural homologies between (t-)PAs isolated from various species. The present approach should also apply to various other classes of proteins, allowing the generation of monoclonal antibodies, against conserved epitopes, which could not be raised in wild-type animals because of their "self-antigen" nature.
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PMID:Generation of monoclonal antibodies against autologous proteins in gene-inactivated mice. 753 37