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)

Plasminogen activators (PA) are implicated in cell migration and tissue remodeling, two components of the bone resorption processes. Using mice with inactivated tissue PA (tPA), urokinase PA (uPA), or type 1 PA inhibitor (PAI-1) genes, we evaluated whether these processes, or their stimulation by parathyroid hormone (PTH) or 1,25-dihydroxyvitamin (1,25[OH]2D3) are dependent on these genes. Two culture models were used, one involving 19-day fetal calvariae, to evaluate the direct resorptive activity of osteoclasis, and the other involving 45Ca-labeled 17-day fetal metatarsals, in which this activity depends on preliminary (pre)osteoclast migration. PTH similarly increased (about 10-fold) PA activity in calvariae from wild-type tPA+/+ and uPA+/+ or deficient uPA-/- and PAI-/- mice; it affected only tPA, not uPA. In tPA-/- bones, the low PA levels, due to uPA, were not influenced by PTH. Calcitonin did not affect PA responses to PTH. No differences were observed between tPA+/+, tPA-/-, uPA+/+, and uPA-/- calvariae for any parameter related to bone resorption (development of lacunae, release of calcium and lysosomal enzymes, accumulation of collagenase, loss of hydroxyproline), indicating similar responses to PTH or calcitonin. The progressive 45Ca release was largely similar in cultures of tPA+/+, tPA-/-, uPA+/+, uPA-/-, PAI+/+, or PAI-/- metatarsals and it was similarly enhanced by PTH or 1,25(OH)2D3. However, uPA-/- metatarsals released 45Ca at a slower rate at the beginning of the cultures, suggesting an impaired recruitment of the (pre)osteoclasts, which migrate at that time from the periosteum into the calcified cartilage. Thus, it appears that the direct resorptive activity of the osteoclasts does not necessitate the presence of either tPA or uPA, but uPA is likely to facilitate the migration of the (pre)osteoclasts toward the mineralized surfaces. Although considerably enhanced by PTH, tPA does not mediate the actions of PTH (nor of 1,25[OH]2D3) evaluated in these models.
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PMID:Bone resorption and response to calcium-regulating hormones in the absence of tissue or urokinase plasminogen activator or of their type 1 inhibitor. 885 51

A pathogenetic role for fibrin deposition and platelet activation in the kidney is thought to play a role in the pathogenesis of acute renal failure (ARF). Thus, some fibrinolytic parameters and platelet function have been studied in 17 patients with ARF and compared to healthy volunteers and subjects with chronic renal failure (CRF). Since serotonin may participate in pathological processes resulting from platelet/vessel wall interactions, its level in the whole blood and plasma was also assayed. In ARF and CRF platelet aggregatory responses in both whole blood and in platelet rich plasma upon stimulation with various agonists (collagen, arachidonic acid, ADP, ristocetin) were lower than those obtained in healthy volunteers. Increased levels of lipoprotein (a), von Willebrand factor (vWF) and fibronectin were found in ARF relative to controls. Protein C activity was significantly lower in patients with ARF. Euglobulin clot lysis time was prolonged in ARF and CRF, reflecting a decreased overall fibrinolytic activity. Activity of tissue plasminogen activator (tPA) inhibitor (PAI) and PAI:Ag were higher in ARF, whereas tPA:Ag, urokinase, tPA/PAI complexes, thrombin-antithrombin complexes (TAT), plasmin-antiplasmin (PAP) complexes, fibrinogen, and F1+2 did not differ between ARF and controls. In CRF elevated levels of TAT, PAP, fibrinogen and prothrombin fragments F1+2 were found, whereas concentration of fibronectin was lowered when compared to controls. In both groups of renal failure patients increased levels of fibrin monomers and d-dimer were found relative to healthy volunteers. Whole blood serotonin was significantly lower, whereas plasma serotonin was significantly higher in patients with ARF and CRF relative to controls. Serotonin uptake and its release from platelets were markedly diminished in patients with ARF and CRF. Chronic renal failure exhibit a slightly different pattern of coagulopathies that acute renal failure.
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PMID:Hemostasis, platelet function and serotonin in acute and chronic renal failure. 887 44

Many lines of evidence support an involvement of urokinase plasminogen activator (uPA) and its type 1 inhibitor (PAI-1) in the migration of a variety of cells, including normal keratinocytes and carcinoma lines. In the present study, uPA expression was found to be a characteristic not just of migratory but also of proliferative keratinocytes. A variety of naturally occurring and experimentally induced epidermal hyperproliferative conditions were examined in mice, including fetal and neonatal epidermis, tape-stripped epidermis, and epidermis from which the hairs had been gently plucked. In all cases, epidermal hyperproliferation was accompanied by elevated levels of uPA mRNA (as measured by in situ hybridization) and activity (as measured by zymography). uPA mRNA was predominantly localized in the basal and immediately suprabasal cells, which constitute the proliferative population. To determine whether a PAI was concomitantly elevated, in situ hybridization for PAI-1 and PAI-2 was performed. PAI-2 but not PAI-1 mRNA was detected in fetal and neonatal epidermis, localized in the spinous layers. Although mRNAs for both inhibitors were induced by tape-stripping or hair-plucking, their distribution was more focal and more transient than that of uPA mRNA. These findings show that uPA, but not its usual inhibitors, is consistently elevated in the proliferative population of keratinocytes in a diverse range of hyperproliferative states. Two hypotheses are suggested by these data: (a) uPA may play a regulatory role in the activation of epidermal proliferation; or (b) uPA may be involved in the vertical migration of keratinocytes that must accompany increased cell proliferation.
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PMID:Modulation of the plasminogen activator cascade during enhanced epidermal proliferation in vivo. 895 48

Pemphigus vulgaris (PV) is caused by autoantibodies against desmosomes and is characterized by intra-epidermal blisters. The pathology of PV has been linked with plasminogen activation in lesional epidermis. The plasminogen activator system (PA system) consists of urokinase-type plasminogen activator (uPA), tissue-type PA (tPA), as well as the two types of plasminogen activator inhibitors (PAI-1 and PAI-2). In keratinocytes, uPA binds to a specific cell surface receptor for uPA (uPA-R = CD87) in an autocrine manner. Cell-bound uPA is regulated by PAIs. The central PA system component plasminogen, which is present in plasma and interstitial fluids, is bound to the keratinocyte surface via plasmin(ogen) binding sites, where it can be activated by uPA-R-bound uPA. Cell surface-associated plasmin then mediates pericellular proteolysis. As the topographical organization of the distinct PA system components in lesional epidermis of PV remained elusive, we have performed the present immunohistological analysis of lesional and non-lesional epidermis of PV. In keratinocytes directly involved in the epidermal split formation, plasmin(ogen) was stained in nine of 10 cases, uPA-R and uPA in four of 10 cases and PAI-2 in seven of 10 cases. Together, acantholytic plasmin(ogen)+ keratinocytes appeared in three different phenotypes: uPA-R+/uPA+ and PAI-2+, uPA-R-/uPA- and PAI-2+, as well as uPA-R-/uPA- and PAI-2-. Our findings demonstrate that, in acantholytic keratinocytes of PV, PAs and PAIs appear as differentially regulated components of the PA system.
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PMID:Plasminogen activator system in pemphigus vulgaris. 897 72

When cultured in type I collagen gels, two kidney-derived cell lines, Madin-Darby canine kidney (MDCK) cells and murine inner medullary collecting duct (mIMCD3) cells, from branching tubular structures in the presence of Swiss 3T3 conditioned medium, in which hepatocyte growth factor (HGF) is the major branching tubule inducing factor. However, upon incubation with transforming growth factor-beta (TGF-beta) in the presence of 3T3 conditioned medium, MDCK tubulogenesis and branching was markedly inhibited. In contrast, mIMCD3 cells, which are much less susceptible to growth and tubulogenesis inhibition by TGF-beta, formed long straight tubulelike structures in presence of TGF-beta, suggesting a dissociation between tubulogenesis and branching morphogenesis. Interestingly, those long tubules that did branch often superficially resembled the early branching ureteric bud in embryonic kidneys. Quantitation of branching events revealed a selective branch-inhibiting effect of TGF-beta on mIMCD3 cells at concentrations between 0.02 and 2 ng/ml. There was no qualitative or quantitative difference among TGF-beta 1, -beta 2, and -beta 3 on inhibition of branching events, suggesting existence of potentially redundant mechanisms for modulating branching morphogenesis. Concentrations of TGF-beta that resulted in long nonbranching tubules also altered the profile of extracellular matrix-degrading proteases and their inhibitors expressed by developing tubules. Ratios of urokinase type plasminogen activator (u-PA) to plasminogen activator inhibitor (PAI-l) and matrix metalloprotease (MMP)-1 to tissue inhibitor of metalloprotease (TIMP)-1 were both markedly decreased. In addition, apart from a direct effect on epithelial cell branching morphogenesis, TGF-beta downregulated the expression of HGF mRNA in Swiss 3T3 cells. Thus TGF-beta exerts at least three distinct effects relevant to tubulogenesis and branching morphogenesis inhibition of branching morphogenesis alone (mIMCD3 cells), inhibition of both tubulogenesis and branching morphogenesis (MDCK cells), and inhibition of the expression of growth factor which induce tubulogenesis and branching morphogenesis (3T3 cells). In the context of epithelial tissue development, which requires tightly regulated branching tubulogenesis of epithelial cells, the data suggest a model where branching patterns are regulated by a precise temporal and spatial balance between branching morphogens such as HGF and inhibitory morphogens such as members of the TGF-beta superfamily [e.g., TGF-beta isoforms, certain bone morphogenetic proteins].
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PMID:Transforming growth factor-beta selectively inhibits branching morphogenesis but not tubulogenesis. 903 60

Endothelial cells synthesize and secrete PA and PAI, and thus provide anticoagulant and procoagulant regulatory mechanisms, respectively. Both plasminogen and plasminogen activators (t-PA and u-PA) bind to specific cellular receptors; assembly of components of the fibrinolytic system at the endothelial cell surface results in stimulation of fibrinolytic activity. Several mechanisms contribute to this stimulation, eg, enhanced plasminogen activation by t-PA or u-PA, enhanced conversion of scu-PA to tcu-PA, and impaired inhibition of plasmin by alpha2-antiplasmin or of PAs by PAIs. Thus, the endothelial cell surface serves as a focal point for plasmin generation.
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PMID:Endothelium in hemostasis and thrombosis. 905 Aug 19

Comparison of the amino acid sequence of the chicken and human urokinase-type plasminogen activators (uPAs) revealed that the putative PAI-binding site found in the variable region 1 (VR1) loop of mammalian PAs is absent in the homologous region of ch-uPA. ch-uPA, unlike mammalian PAs, also appears to be refractory to inhibition by human PAIs and as a naturally occurring PAI-resistant variant, constitutes a unique model system for assessing the functional relevance of the PAI-binding site. Therefore, we molecularly constructed a ch-uPA, ch-uPA(RRHR), which contains the putative PAI-binding motif RRHR (residues 192-195) in its VR1 loop. As a result of this substitution, the second-order rate constant of inhibition of PAI-1 increased approximately 700-fold from 4.50 x 10(4) M(-1) x s(-1) for wild-type ch-uPA to 3.02 x 10(7) M(-1) x s(-1) for ch-uPA(RRHR), and the ability to form SDS-stable, uPA-PAI-1 complexes increased approximately 1000-fold. Furthermore, the interaction of ch-uPA(RRHR) with PAI-2 was also substantially enhanced, while the interaction with other members of the serine proteinase inhibitor superfamily, protein nexin 1, alpha1-PI, and C1-inhibitor, was unaffected indicating that the RRHR motif is not a general serine proteinase inhibitor binding site. Finally, we show that extracellular matrix degradation by cells expressing ch-uPA(RRHR) is inhibited by PAI-1 in a dose-dependent manner, while matrix breakdown by cells expressing wild-type ch-uPA is unaffected by PAI-1. Thus acquisition of sensitivity to PAI-1 through a structural motif that enhances the specificity of the protease-inhibitor interaction confers to ch-uPA an added level of regulation in the context of the degradative cellular phenotype.
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PMID:Introduction of an RRHR motif into chicken urokinase-type plasminogen activator (ch-uPA) confers sensitivity to plasminogen activator inhibitor (PAI)-1 and PAI-2 and allows ch-uPA-mediated extracellular matrix degradation to be controlled by PAI-1. 909 24

Suppression of the fibrinolytic activity plays an important role in the prevention of hemorrhage during pregnancy and labor. A hypofibrinolytic and hypercoagulable state may be established in the placenta during pregnancy. However, little infraction is present in the normal placenta. This evidence shows that placenta maintains the fibrinolytic activity in spite of hypercoagulable state. As there is a high amount of APC in the placenta, APC is thought to be involved in fibrinolysis of placenta. Thus, we studied the role of APC on fibrinolysis in placenta. (1) uPA activity of cell membrane reappears after incubation with uPA/PAI-1 complex and a large amount of APC by flow cytometry, (2) APC was made PAI-1/APC complex after incubation of uPA/PAI-1 complex with APC. Our results suggest that APC is the important substance for fibrinolysis in the placenta by decreasing of PAI activity.
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PMID:Relationship of urokinase type plasminogen activator, plasminogen activator inhibitor type 1 and activated protein C in fibrinolysis of human placenta. 911 54

During cardiopulmonary bypass (CPB) mechanical stress and the contact of blood with artificial surfaces lead to the activation of pro- and anticoagulant systems and the complement cascade, and to changes in cellular components. This phenomenon causes the "postperfusion-syndrome", with leukocytosis, increased capillary permeability, accumulation of interstitial fluid, and organ dysfunction. In this study, we focused on the influence of the extracorporeal circulation, sternotomy, and heparin administration on the activation of coagulation and fibrinolysis. In 15 patients we investigated coagulation parameters before, during and post CPB, i.e., fibrinogen, antithrombin (AT) III, thrombin-antithrombin complex (TAT), prothrombin fragments F1 + 2 (F1 + 2), factor (F) XIIa, tissue factor (TF), and parameters of the fibrinolytic system, i.e., plasmin-antiplasmin-complex (PAP), D-dimer, tissue-plasminogen-activator (tPA), urokinase-type plasminogen activator (uPA), and plasminogen-activator inhibitor type 1 (PAI 1). The results demonstrate distinct alterations in the above mentioned parameters. Despite administration of a high dose of heparin (activated clotting time [ACT] > 450s) combined with a low dose of aprotinin, activation of the coagulation and fibrinolytic pathways was observed. We found this activation was mainly caused by CPB and not by sternotomy. The activation of coagulation was due to foreign surface contact (F XII => F XIIa) as well as to an effect of tissue factor release in the late phase of CPB. The enhanced fibrinolytic activity during CPB was, at least in part, caused by tPA and was followed by PAI 1 release.
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PMID:Changes in coagulation and fibrinolytic parameters caused by extracorporeal circulation. 924 50

The clinical oncology realizes that the classical approach with systemic adjuvant chemo- and hormonal therapies is not sufficient and will be challenged by cellular and molecular structures which reflect the targets for new therapeutic approaches. These targets are key proteins involved in the signal transduction cascade. In human tumors these proteins have either lost their biological functionality by oncogenic mutations or are constitutively activated. The molecular classification of primary breast cancer was performed by assessing the following factors: estrogen- and progesterone receptors, ERbB-2 mutated p53, uPA, PAI-I, VEGF, DNA-Index and S-Phase. These factors are of prognostic and predictive value.
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PMID:[Molecular factors determine primary and secondary therapy of breast carcinoma]. 938 15


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