Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 SspB cysteine protease of Staphylococcus aureus is expressed in an operon, flanked by the sspA serine protease, and sspC, encoding a 12.9-kDa protein of unknown function. SspB was expressed as a 40-kDa prepropeptide pSspB, which did not undergo autocatalytic maturation. Activity of pSspB was reduced compared with 22-kDa mature SspB, but it was equivalent to mature SspB after incubation with SspA, which specifically removed the pSspB N-terminal propeptide. SspC abrogated the activity of pSspB when incubated in a 1:1 complex but had no effect on SspA or papain. Activity of the pSspB.SspC complex was restored when incubated with SspA, and SspC was cleaved by SspA but not pSspB. Thus, SspC maintains pSspB as an inert zymogen, and SspA is required for removal of the propeptide and inactivation of SspC. Like the papain protease family, SspB cleaved substrates with a hydrophobic amino acid at P2 but had a strong preference for arginine at P1. It did not cleave casein, serum albumin, IgG, or IgA, but it promoted detachment of cultured keratinocytes and cleaved fibronectin and fibrinogen at sites recognized by urokinase plasminogen activator and plasmin, respectively. It also processed high molecular weight kininogen in a manner resembling plasma kallikrein. Thus, SspB exhibits a novel maturation mechanism and mimics the specificity of plasma serine proteases.
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PMID:Identification of a novel maturation mechanism and restricted substrate specificity for the SspB cysteine protease of Staphylococcus aureus. 1220 24

The influence of the hyaluronan-binding protease (PHBSP), a plasma enzyme with FVII- and pro-urokinase-activating potency, on components of the contact phase (kallikrein/kinin) system was investigated. No activation or cleavage of the proenzymes involved in the contact phase system was observed. The pro-cofactor high molecular weight kininogen (HK), however, was cleaved in vitro by PHBSP in the absence of any charged surface, releasing the activated cofactor and the vasoactive nonapeptide bradykinin. Glycosoaminoglycans strongly enhanced the reaction. The cleavage was comparable to that of plasma kallikrein, but clearly different from that of coagulation factor FXIa. Upon extended incubation with PHBSP, the light chain was further processed, partially removing about 60 amino acid residues from the N-terminus of domain D5 of the light chain. These cleavage site(s) were distinct from plasma kallikrein or FXIa cleavage sites. PHBSP and, more interestingly, also plasma kallikrein could cleave low molecular weight kininogen in vitro, indicating that domains D5H and D6H are no prerequisite for kininogen cleavage. PHBSP was also able to release bradykinin from HK in plasma where the pro-cofactor circulates predominantly in complex with plasma kallikrein or FXI. In conclusion, PHBSP represents a novel kininogen-cleaving and bradykinin-releasing enzyme in plasma that shares significant catalytic similarities with plasma kallikrein. Since they are structurally unrelated in their heavy chains (propeptide), their similar in vivo catalytic activities might be directed at distinct sites where PHBSP could induce processes that are related to the kallikrein/kinin system.
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PMID:The hyaluronan-binding serine protease from human plasma cleaves HMW and LMW kininogen and releases bradykinin. 1245 40

Understanding the importance and physiologic activity of the plasma kallikrein/kinin system (KKS) has been thwarted by the absence of an inclusive theory for its assembly and activation. The contact activation hypothesis describes the assembly and activation of this system in test tubes and disease states, but not under physiologic circumstances. Recent investigations have indicated a new cohesive hypothesis for understanding physiologic activation of this system. Prekallikrein (PK) and factor XI (FXI) through high molecular weight kininogen (HK) assemble on a co-localized, multiprotein receptor complex on endothelial cells that consists of at least cytokeratin 1 (CKI), gClqR, and urokinase plasminogen activator receptor (muPAR). When assembled on these proteins, prekallikrein becomes activated to kallikrein by the membrane-expressed enzyme prolylcarboxypeptidase (PRCP). Formed kallikrein then activates factor XII (FXII) for amplification of its activation and single chain urokinase. The plasma kallikrein/kinin system may serve as a physiologic counterbalance to the plasma renin angiotensin system (RAS) by lowering blood pressure and preventing thrombosis. Insights into the integrated role of these two systems may afford the development of novel therapeutic drugs to manage hypertension and thrombosis.
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PMID:Assembly and activation of the plasma kallikrein/kinin system: a new interpretation. 1248 98

Plasminogen activator inhibitor-1 (PAI-1) and two-chain high molecular weight kininogen (HKa) exert anti-adhesive properties in vitronectin-dependent cell adhesion. Here, the hypothesis was tested that these anti-adhesive components promote apoptosis in vascular cells. PAI-1 or HKa induced a 2- to 3-fold increase in apoptosis of human umbilical-vein endothelial cells (HUVEC) and vascular smooth muscle cells (VSMC) adherent to vitronectin, as determined by annexin V-FACS assay, similar to alphav-integrin inhibitor cyclo-(Arg-Gly-Asp-D-Phe-Val)-peptide (cRGDfV). Apoptosis occurred after 12 h incubation and was attributable to caspase 3 activation that in turn induced DNA fragmentation. Induction of apoptosis strongly correlated with the anti-adhesive effect of PAI-1 and HKa on these cells. In contrast, PAI-1 and HKa did not affect fibronectin-dependent adhesion or cell survival. uPA did not influence apoptosis in vitronectin- or fibronectin-adherent cells. In atherosclerotic vessel sections, congruent distribution of vitronectin, PAI-1, HK, and of components of the urokinase plasminogen activator/receptor system with apoptotic cells lining foam cell lesions was demonstrated by immunostaining. These results indicate that inhibition of vitronectin-dependent cell adhesion through PAI-1 and HKa correlates with apoptosis induction in vascular cells mediated through the caspase 3 pathway. Co-distribution of apoptosis with plasminogen activation system components in atherosclerosis exemplifies the significance of anti-adhesive mechanisms and apoptosis for tissue remodeling, such as in neointima development.
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PMID:Induction of apoptosis in vascular cells by plasminogen activator inhibitor-1 and high molecular weight kininogen correlates with their anti-adhesive properties. 1271 93

Leukocyte recruitment to sites of inflammation, infection or vascular injury is a complex event, depending on a tightly coordinated sequence of leukocyte-endothelial- and leukocyte-platelet interactions, which are controlled by the expression and activation of various adhesion receptors and protease systems. The present review will focus on novel aspects of the regulation of integrin-dependent leukocyte adhesion by haemostatic factors and bacterial products. In particular, after a short overview of leukocyte recruitment, the review (i) will focus on the crosstalk between haemostatic factors and adhesion molecules with respect to leukocyte extravasation based on the paradigms of the urokinase receptor and high molecular weight kininogen, (ii) will provide information on novel mechanisms for the regulation of leukocyte recruitment by bacterial proteins, on the basis of the anti-inflammatory role of Staphylococcus aureus extracellular adhesive protein and (iii) will draw attention to the junctional adhesion molecules, a novel family of adhesive receptors that are counter-receptors for leukocyte integrins and mediate vascular cell interactions. The better understanding of the interactions between vascular cells and particularly of integrin-dependent leukocyte adhesion may lead to the development of novel therapeutical concepts in inflammatory vascular disorders.
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PMID:New aspects of integrin-mediated leukocyte adhesion in inflammation: regulation by haemostatic factors and bacterial products. 1277 93

The urokinase plasminogen activator receptor (uPAR) is a multifunctional, GPI-linked receptor that modulates cell adhesion/migration and fibrinolysis. We mapped the interaction sites between soluble uPAR (suPAR) and high molecular mass kininogen (HK). Binding of biotin-HK to suPAR was inhibited by HK, 56HKa, and 46HKa with an IC50 of 60, 110, and 8 nm, respectively. We identified two suPAR-binding sites, a higher affinity site in the light chain of HK and 46HKa (His477-Gly496) and a lower affinity site within the heavy chain (Cys333-Lys345). HK predominantly bound to suPAR fragments containing domains 2 and 3 (S-D2D3). Binding of HK to domain 1 (S-D1) was also detected, and the addition of S-D1 to S-D2D3 completely inhibited biotin-HK or -46HKa binding to suPAR. Using sequential and overlapping 20-amino acid peptides prepared from suPAR, two regions for HK binding were identified. One on the carboxyl-terminal end of D2 (Leu166-Thr195) blocked HK binding to suPAR and to human umbilical vein endothelial cells (HUVEC). This site overlapped with the urokinase-binding region, and urokinase inhibited the binding of HK to suPAR. A second region on the amino-terminal portion of D3 (Gln215-Asn255) also blocked HK binding to HUVEC. Peptides that blocked HK binding to uPAR also inhibited prekallikrein activation on HUVEC. Therefore, HK interacts with suPAR at several sites. HK binds to uPAR as part of its interaction with its multiprotein receptor complex on HUVEC, and the biological functions that depend upon this binding are modulated by urokinase.
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PMID:Mapping the interaction between high molecular mass kininogen and the urokinase plasminogen activator receptor. 1476 80

Leukocyte recruitment to sites of inflammation, infection or vascular injury is a complex event that is orchestrated by a tightly coordinated sequence of interactions between leukocytes and cells of the vessel wall, especially endothelial cells. These interactions are controlled by the expression and activation of various adhesion receptors and protease systems. This review will focus on novel aspects of the regulation of integrin-dependent leukocyte adhesion by haemostatic factors. Here, so-called non-haemostatic properties of endogenous proteins such as high molecular weight kininogen, urokinase receptor, urokinase, as well as plasminogen and its cleavage product angiostatin in leukocyte adhesion and transmigration will be summarized. The crosstalk between haemostatic factors and inflammatory reactions may contribute to a better understanding of inflammatory vascular disorders and to the development of novel therapeutical concepts.
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PMID:Integrin-mediated leukocyte adhesive interactions: regulation by haemostatic factors. 1571 18

Multiple myeloma (MM), a B-cell malignancy characterized by proliferation of monoclonal plasma cells remains incurable. Murine plasma cell tumors share common features with human MM. We used two cell lines (B38 and C11C1) derived from P3X63Ag8 myeloma cells. The new cell lines were implanted subcutaneously in the strain of origin (Balb/c mice) and used as a model to monitor the effects of C11C1 monoclonal antibody (mAb) to kininogen (HK). We assessed their behavior by intraperitoneal and subcutaneous implantation, by implanting them together and by treating B38-MM with purified mAb C11C1. We evaluated growth, microvascular density (MVD), and cellular expression of urokinase-type plasminogen activator-receptor (uPAR), fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), bradykinin-1 receptor (B1R), bradykinin-2 receptor (B2R) and HK. We found that both MM-cell-lines are uPAR positive, that mAb C11C1 inhibits its own tumor growth in vivo, slows down B38-MM growth rate when both MM are implanted together and when mAb C11C1 is injected intraperitoneally. MAb C11C1-treated-MM showed decreased MVD and HK binding in vivo without FGF-2, B1R or B2R expression changes. We propose that the B38-extramedullary-myeloma-model is a useful tool to study the interactions of this hematopoietic tumor and its environment and that mAb C11C1 may improve the efficacy of conventional MM treatment with minimal side effects.
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PMID:Multiple myeloma in a murine syngeneic model:modulation of growth and angiogenesis by a monoclonal antibody to kininogen. 1618 87

In two-dimensional (2-D) culture systems, we have previously shown that cleaved two-chain high-molecular-weight kininogen (HKa) or its domain 5 induced apoptosis by disrupting urokinase plasminogen activator (uPA) receptor (uPAR)-integrin signal complex formation. In the present study, we used a three-dimensional (3-D) collagen-fibrinogen culture system to monitor the effects of HKa on tube formation. In a 3-D system, HKa significantly inhibited tube and vacuole formation as low as 10 nM, which represents 1.5% of the physiological concentration of high-molecular-weigh kininogen (660 nM), without apparent apoptosis. However, HKa (300 nM) completely inhibited tube formation and increased apoptotic cells about 2-fold by 20-24 h of incubation. uPA-dependent ERK activation and uPAR internalization regulate cell survival and migration. In a 2-D system, we found that exogenous uPA-induced ERK phosphorylation and uPAR internalization were blocked by HKa. In a 3-D system, we found that not only uPA-uPAR association but also the activation of ERK were inhibited by HKa. HKa disrupts the uPA-uPAR complex, inhibiting the signaling pathways, and also inhibits uPAR internalization and regeneration to the cell surface, thereby interfering with uPAR-mediated cell migration, proliferation, and survival. Thus, our data suggest that the suppression of ERK activation and uPAR internalization by HKa contributes to the inhibition of tube formation. We conclude that in this 3-D collagen-fibrinogen gel, HKa modulates the multiple functions of uPAR in endothelial cell tube formation, a process that is closely related to in vivo angiogenesis.
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PMID:The inhibitory effect of HKa in endothelial cell tube formation is mediated by disrupting the uPA-uPAR complex and inhibiting its signaling and internalization. 1849 8

Inflammation is an adaptive response to damage of vascularized tissues, which develops according to a stereotyped sequence governed by the local production of the so-called "chemical mediators of inflammation". Here we review the evidences indicating a role of the plasminogen activation system in the regulation of all the phases of the inflammation process. Plasminogen activation controls the formation of complement anaphylotoxins (responsible for vasodilatation, increase of venular permeability and leukocyte chemotaxis) and of bradykinin (which accounts for vasodilatation, increase of venular permeability and pain) by regulating the plasma contact system. The urokinase plasminogen activator and its cellular receptor, expressed on the surface of human leukocytes, provide a functional unit that, by regulating interaction of leukocytes with extracellular matrix, as well as its degradation, is critical for the migration of leukocytes and for their movement in the damaged tissues. By preventing excess fibrin accumulation in inflamed tissues, the plasminogen activation system also governs the proper evolution of the inflammatory exudates and prevents the possibility of a shift from acute to chronic inflammation.
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PMID:The plasminogen activation system in inflammation. 1850 38


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