Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cellular receptor for urokinase-type plasminogen activator (uPAR) binds pro-urokinase (pro-uPA) and facilitates its conversion to enzymatically active urokinase (uPA). uPA in turn activates surface-bound plasminogen to plasmin, a process of presumed importance for a number of biologic processes including cell migration and resolution of thrombi. We have previously shown that uPAR is expressed on the plasma membrane of circulating neutrophils, and we now report that stimulation with phorbol myristate acetate (PMA), FMLP, or tumor necrosis factor-alpha results in a rapid increase in the expression of uPAR. This process is accompanied by an increased cell-associated plasminogen activation after preincubation of neutrophils with pro-uPA in vitro. By subcellular fractionation of unstimulated neutrophils, 50% of uPAR is recovered in fractions containing latent alkaline phosphatase, corresponding to an intracellular compartment of easily mobilizable secretory vesicles distinct from both primary and specific granules, whereas the remaining 50% of uPAR is associated with a compartment eluting close to the specific granules. In contrast, the ligand pro-uPA is primarily (approximately 80%) found in the specific granules, but small amounts of pro-uPA/uPA (approximately 20%) coelute with latent alkaline phosphatase. Stimulation of neutrophils with FMLP results in translocation of uPAR as well as of pro-uPA from the secretory vesicles, whereas stimulation with PMA is required to translocate material from specific granules. Flow cytometry of neutrophils saturated with exogenous diisopropyl fluorophosphate-uPA shows a large excess (approximately 90%) of unoccupied uPAR on resting as well as FMLP- and PMA-stimulated neutrophils, suggesting a possible role for exogenous pro-uPA in providing neutrophils with a potential for plasminogen activation. These processes may be important for neutrophil extravasation and migration through extracellular matrix and for the contribution of neutrophils to resolution of thrombi.
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PMID:The receptor for urokinase-type plasminogen activator and urokinase is translocated from two distinct intracellular compartments to the plasma membrane on stimulation of human neutrophils. 829 41

Proteolytic inactivation of serine protease inhibitors (serpins) by neutrophil elastase (HNE) is presumed to contribute to the deregulation of plasma cascade systems in septic shock. Here, we report a supplementary approach to construct serpins, in our case C1 inhibitor, that are resistant to catalytic inactivation by HNE. Instead of shifting the specificity of alpha 1-antitrypsin towards the proteases of the contact activation and complement systems, we attempted to obtain a C1 inhibitor species which resists proteolytic inactivation by HNE. 12 recombinant C1 inhibitor variants were produced with mainly conservative substitutions at the cleavage sites for HNE, 440-Ile and/or 442-Val. Three variants significantly resisted proteolytic inactivation, both by purified HNE, as well as by activated neutrophils. The increase in functional half-life in the presence of FMLP-stimulated cells was found to be 18-fold for the 440-Leu/442-Ala variant. Inhibitory function of these variants was relatively unimpaired, as examined by the formation of stable complexes with C1s, beta-Factor XIIa, kallikrein, and plasmin, and as determined by kinetic analysis. The calculated association rate constants (k(on)) were reduced twofold at most for C1s, and appeared unaffected for beta-Factor XIIa. The effect on the k(on) with kallikrein was more pronounced, ranging from a significant ninefold reduction to an unmodified rate. The results show that the reactive centre loop of C1 inhibitor can be modified towards decreased sensitivity for nontarget proteases without loss of specificity for target proteases. We conclude that this approach extends the possibilities of applying recombinant serpin variants for therapeutic use in inflammatory diseases.
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PMID:Recombinant C1 inhibitor P5/P3 variants display resistance to catalytic inactivation by stimulated neutrophils. 845 33

We have previously reported that the serine protease plasmin triggers chemotaxis in human peripheral monocytes, but not in polymorphonuclear leukocyte. We now show that the structurally related lipoprotein(a) (Lp[a]) as well as recombinant apolipoprotein(a) (apo[a]) trigger chemotactic responses in human monocytes equipotent to that observed with the standard chemoattractant FMLP. The chemotactic effects of Lp(a) and FMLP were additive. Low density lipoprotein (LDL) did not elicit any significant chemotactic response nor did it interfere with that triggered by Lp(a). As assessed by checkerboard analysis, Lp(a)-mediated monocyte locomotion was a true chemotaxis. Both plasminogen as well as catalytically inactivated plasmin inhibited monocyte migration elicited by Lp(a), suggesting binding of Lp(a) to plasminogen binding sites. Lp(a)-mediated signaling proceeds through a pertussis toxin-sensitive guanosine triphosphate (GTP)-binding protein and activation of protein kinase C as implicated by the effects of 1-O-hexadecyl-2-O-methyl-rac-glycerol and chelerythrine. Lp(a) induced generation of guanosine 3',5'-cyclic monophosphate (cGMP), apparently crucial for the Lp(a)-mediated chemotaxis, because an inhibitor of soluble guanylyl cyclase, LY83583, reduced both the Lp(a)-induced cGMP formation as well as the monocyte migration. The latter effect of LY83583 was antagonized by the stable cGMP analog 8-pCPT-cGMP. The data indicate that Lp(a) triggers chemotaxis in human monocytes by way of a cGMP-dependent mechanism. Our findings may have important implications for the atherogenesis associated with elevated levels of Lp(a).
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PMID:Lipoprotein(a) is a potent chemoattractant for human peripheral monocytes. 929 39

Plasmin triggers chemotaxis and NF-kappa B- and AP-1-mediated proinflammatory gene expression in human peripheral monocytes (PM). Compared with macrophages and dendritic cells, PM express mainly the peroxisome proliferator-activated receptor (PPAR) gamma and traces of PPAR alpha as detected by semiquantitative RT-PCR and immunoblotting. The PPAR gamma agonist ciglitazone, but not the PPAR alpha agonist clofibric acid, concentration-dependently inhibited the plasmin-, but not the FMLP-induced PM chemotaxis. Similarly, release of interleukin (IL)-1 alpha, IL-1 beta and tumor necrosis factor (TNF)-alpha from plasmin-stimulated PM was concentration-dependently inhibited by ciglitazone, but not by clofibric acid, while the LPS-induced TNF-alpha release remained unaffected by any of both PPAR agonists. Ciglitazone activates PPAR gamma as shown by a novel surface plasmon resonance analysis and inhibits the plasmin-induced activation of NF-kappa B and AP-1. It also inhibits p38 MAPK phosphorylation essential for the plasmin-induced PM chemotaxis and gene activation. Thus, activation of PPAR gamma by ciglitazone may allow controLling of the plasmin-mediated recruitment and activation of PM at sites of inflammation.
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PMID:Ciglitazone inhibits plasmin-induced proinflammatory monocyte activation via modulation of p38 MAP kinase activity. 1219