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

Fibroblasts as well as several other cell types, secrete a number of protease inhibitors into their culture media. Among these inhibitors are the protease nexins, a class of proteins which covalently bind serine proteases, thereby inactivating their specific targets. Protease nexin-I, first discovered in human foreskin fibroblasts, binds thrombin, plasmin, and urokinase with high affinity, forming covalently linked complexes. Human fibroblasts bind complexes of protease nexin-I and its target protease via a cell-surface, high-affinity receptor. We have analyzed a number of characteristics of this receptor, and found them to be typical of class II receptors in general. At 4 degrees C binding of PN-I:protease complexes was competed by heparin. In addition, binding was independent of the particular protease bound to the PN-I; purified complexes of PN-I with thrombin or urokinase competed equipotently for [125]I-thrombin:PN-I binding. As the pH of the binding buffer was lowered, binding to cells increased. A twofold increase in binding was attained by lowering the pH from 7.5 to 4.5. This phenomenon was not due to irreversible, pH-induced changes to either the cell surface or the labeled complexes. At 37 degrees C, the removal of labeled complexes from culture medium was rapid; approximately 80% was removed by 4 hours under given conditions. The internalization of complexes was also very rapid, with an estimated ke (endocytic rate constant) of 1.0 min-1. At neutral pH, fibroblasts bind complexes in a saturable manner. Scatchard analysis yields a receptor number of 250,000 per cell and a Kd of 1 nM.
 ...
PMID:Characterization of the receptor for protease nexin-I:protease complexes on human fibroblasts. 303 24

Protease nexin-I (PN-I, Mr approximately 43,000) is representative of a newly described class of cell-secreted protease inhibitors. PN-I has been purified to apparent homogeneity, partially sequenced, and monospecific antibodies have been raised against it. PN-I is a potent inhibitor of urokinase, thrombin, plasmin, and trypsin. In addition, cells have specific receptors that mediate the uptake of covalently linked complexes formed between PN-I and its protease substrates. In the present studies, we have investigated the relationship between human PN-I and a protease inhibitor derived from C6 glioma cells in culture that has neurite-promoting activity. On the basis of co-purification on heparin-Sepharose, identical molecular weight, antibody cross-reactivity, and receptor cross-reactivity, we conclude that PN-I and the glioma-cell-derived inhibitor are equivalent molecules.
 ...
PMID:The glioma cell-derived neurite promoting activity protein is functionally and immunologically related to human protease nexin-I. 304 Jul 80

The protease nexins (PN-I, Mr approximately 38,000; PN-II, Mr approximately 95,000; and PN-III, Mr approximately 31,000) are recently described cell-secreted proteins that selectively link to regulatory serine proteases in the extracellular environment and mediate their cellular binding, internalization, and degradation. In the present studies we compared the protease nexins with respect to protease specificity, heparin sensitivity, and general mode of action. By competitive binding assays using [125I]-thrombin, [125I]-nerve growth factor-gamma (125I-NGF-gamma), and [125I]-epidermal growth factor binding protein (125I-EGF-binding protein), we characterized the nexins in terms of protease specificity and determined that PN-I links to and mediates the cellular binding of thrombin or urokinase, whereas PN-II and PN-III preferentially link to and mediate the cellular binding of the EGF binding protein and NGF-gamma, respectively. In addition, whereas the ability of PN-I to link to thrombin is strongly modulated by heparin, PN-II and PN-III are essentially unaffected by heparin. The linkage of each of the nexins to their respective proteases requires the catalytic site serine of the protease, judged by the inability of diisopropylphospho (DIP) derivatives of the proteases tested to link to their respective nexins. Subsequent to linkage, the nexin:protease complexes are bound to cells, rapidly internalized, and ultimately degraded via a monensin-sensitive apparently lysosomal pathway, although each nexin:protease complex is degraded at its own characteristic rate. Importantly, the protease nexins provide the major pathway through which human fibroblasts interact with each of the serine proteases studied. Taken together, these data suggest that the nexins are a unique class of cell-secreted proteins that enable cells to monitor and selectively regulate specific serine proteases in their environment.
 ...
PMID:Protease nexins: cell-secreted proteins that mediate the binding, internalization, and degradation of regulatory serine proteases. 631