Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of platelets with human leukocyte elastase causes a rapid loss in response to von Willebrand factor and a biphasic loss in response to thrombin, first rapid then more slowly. The rapid phase corresponds to cleavage of a 45-kDa glycopeptide from the extracellular end of membrane glycoprotein GPIb. Longer treatment removes 80-kDa and 90-kDa glycopeptides and a glycopeptide corresponding to the major part of GPV. The 45-kDa and 90-kDa species could be obtained by elastase treatment of glycocalicin, the major proteolytic cleavage product of GPIb. Polyclonal rabbit antibodies against the purified 45-kDa glycopeptide had the same effect on the action of von Willebrand factor and thrombin on platelets as cleavage of GPIb by elastase. These results indicate that both the von Willebrand factor and thrombin binding sites on GPIb are located in the same region on the outside of the molecule. Thrombin activation of platelets involves at least two receptors, one on the 45-kDa glycopeptide, which when occupied causes an increase in the speed of response of the platelets to the cleavage of the second. GPV, a candidate for the second receptor, is a hydrophobic glycoprotein that is cleaved from the platelet membrane by several proteases. Proteases that do not activate platelets but degrade the second receptor remove larger fragments from GPV than do proteases such as thrombin or trypsin which activate platelets.
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PMID:Structure and function of platelet membrane glycoproteins Ib and V. Effects of leukocyte elastase and other proteases on platelets response to von Willebrand factor and thrombin. 293 56

Two major membrane receptors implicated in the adhesive properties of blood platelets are the GPIb-IX complex, a receptor for subendothelial von Willebrand factor, and the alpha IIb beta 3 integrin, the receptor for plasma fibrinogen. We have evaluated how the biological activities of these receptors can be potentially modulated through limited proteolysis when platelets are exposed to the serine-proteinases secreted by activated polymorphonuclear neutrophils, i.e., leukocyte elastase (EL) and cathepsin G (CG). CG can activate the alpha IIb beta 3 integrin through intracellular metabolic pathways, but has no direct proteolytic activity on the receptor subunits. By contrast, EL does not activate the platelet metabolism, but specifically cleaves a short peptide sequence within the alpha IIb subunit, and this cleavage occurs in parallel with an up-regulation of the activity of the fibrinogen receptor. On another hand, both EL and CG cleave the amino-terminal portion of the GPIb alpha subunit of the GPIb-IX receptor, eliminating the binding site for von Willebrand factor and diminishing the capacity of platelets to interact with this adhesion protein. Thus, neutrophil proteinases have the potential to regulate the activity of platelet adhesion receptors, and such experimental observations may prove to be relevant in vivo in various pathological conditions.
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PMID:Regulation of the structure and activity of platelet adhesion receptors by leukocyte proteinases. 817 29

In this study, we show that the platelet surface expression of glycoprotein (GP) V is regulated by two independent mechanisms. While confirming that both thrombin and neutrophil elastase proteolyse GPV, we show that neutrophil cathepsin G, thrombin receptor activating peptide (TRAP), and a combination of ADP and epinephrine can each result in a decrease in the platelet surface expression of GPV by a nonproteolytic mechanism: a cytoskeletal-mediated redistribution of platelet surface GPV to the surface-connected canalicular system (SCCS). Four independent lines of evidence documented the nonproteolytic nature of this decrease in the platelet surface expression of GPV. First, flow cytometric studies showed that cathepsin G, TRAP, and ADP/epinephrine decreased the platelet surface expression of GPV without changing the total platelet content of GPV. Second, immunoelectron microscopy directly demonstrated translocation of GPV from the platelet surface to the SCCS. Third, the cathepsin G-, TRAP-, and ADP/epinephrine-induced decreases in platelet surface GPV were fully reversible. Fourth, cytochalasin B, an inhibitor of actin polymerization, completely inhibited the cathepsin G-, TRAP-, and ADP/epinephrine-induced decreases in platelet surface GPV. The cytoskeletal-mediated redistribution of GPV occurred in a whole blood milieu and at physiologic temperatures (37 degrees C) and extracellular calcium concentrations (2 mmol/L). This study also defines the diverse effects on GPV, GPIb, and GPIX of multiple important platelet agonists. Cathepsin G proteolysed platelet surface GPIb alpha, but redistributed platelet surface GPIX and GPV to the SCCS. Thrombin proteolysed platelet surface GPV, but redistributed platelet surface GPIb and GPIX to the SCCS. Both TRAP and ADP/epinephrine redistributed platelet surface GPIb, GPIX, and GPV to the SCCS. Elastase proteolysed platelet surface GPIb alpha and GPV, but, unlike the other agonists tested, neither proteolysed nor redistributed platelet surface GPIX. The experiments with TRAP showed that activation of the seven-transmembrane domain thrombin receptor can result in translocation of GPIb, GPIX, and GPV to the SCCS independently of the GPIb-mediated pathway of thrombin-induced platelet activation. This study also provides two additional lines of support for the recent report that GPV is noncovalently complexed with GPIb and GPIX in the platelet surface membrane. First, although only the GPIb alpha subunit of this putative complex is known to be directly linked to the platelet cytoskeleton via actin-binding protein, cytochalasin B inhibited the ADP/epinephrine-, cathepsin G-, and TRAP-induced decrease in platelet surface GPV. Second, triple labeling flow cytometric experiments showed that, on each individual platelet, the ADP/epinephrine-induced decrease and subsequent return of the platelet surface expression of GPV occurred simultaneously with the decrease and subsequent return of the platelet surface expression of GPIb. In summary, the platelet surface expression of GPV is regulated by two independent mechanisms: proteolysis and a reversible, cytoskeletal-mediated redistribution to the SCCS.
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PMID:The platelet surface expression of glycoprotein V is regulated by two independent mechanisms: proteolysis and a reversible cytoskeletal-mediated redistribution to the surface-connected canalicular system. 860 29