Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Urokinase-type-plasminogen activator (uPA) and its receptor are localized in the vessel wall where they are involved in cellular activation and remodelling processes. Besides the cell surface glycolipid (GPI)-anchored urokinase receptor (uPAR), which binds uPA with high affinity, recent evidence points to the existence of soluble uPAR (suPAR), as well. In the present study, the origin, binding mechanism, and cellular effects of suPAR were examined. Under basal conditions human vascular smooth muscle cells (HVSMC), human umbilical vein endothelial cells (HUVEC), and monocytic cells released 0.1 to 2 ng/mL suPAR, which was increased twofold to fivefold after phorbol ester (PMA) stimulation, as measured by a function-dependent enzyme-linked immunosorbent assay (ELISA). suPAR alone did not bind to HVSMC or HUVEC, but reduced cellular uPA binding by 50% to 70%. However, after removal of GPI-uPAR with phosphatidylinositol-specific phospholipase C, suPAR dose-dependently increased uPA binding by fourfold to fivefold. This increase in binding was completely inhibited by vitronectin (VN) and by a monoclonal antibody against VN, but not by other matrix proteins or antibodies. Thus, VN-mediated uPA binding to cells was regulated by the ratio of soluble to surface-associated uPAR. In a uPAR-deficient cell line (LM-TK-), suPAR increased uPA binding up to 10-fold, whereas the truncated receptor lacking the amino-terminal uPA-binding domain was ineffective. The formation of a ternary uPA/suPAR/VN-complex on the cell surface and the free extracellular matrix could be inhibited by a monoclonal antibody against VN, as well as by plasminogen activator inhibitor-1 (PAI-1). Moreover, VN-mediated binding of the uPA/suPAR-complex led to a fivefold increase in plasminogen activator activity. Through this novel pathway, VN concentrates the uPA/suPAR-complex to cell surfaces and extracellular matrix sites, leading to the accumulation of plasminogen activator activity required for cell migration and tissue remodelling processes.
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PMID:Vitronectin concentrates proteolytic activity on the cell surface and extracellular matrix by trapping soluble urokinase receptor-urokinase complexes. 951 28

The proteolytic cascade involving plasminogen activators and plasmin appears to have an important function in tissue regeneration. We have investigated the expression and cellular localization of urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) as well as plasminogen activation in rat liver regeneration by recruitment of progenitor (oval) cells. Using a model in which surgical partial hepatectomy is combined with feeding of 2-acetylaminofluorene (2-AAF) to induce liver regeneration by proliferation and differentiation of oval cells, expression of uPA, uPAR, and PAI-1 was detected by immunohistochemistry mainly in the duct-like formations of expanding oval cells. Plasminogen activation, as assessed by direct zymography on frozen liver sections, was located over the expanding oval cell populations but not over mature hepatocytes. Plasminogen activation was not detected in control liver. Expression of uPA, uPAR, and PAI-1, as assessed by immunohistochemical and Northern blot analyses, was also observed, when cells located in and in close proximity to the bile epithelial structures were activated to enter DNA-synthesis in response to 2-AAF, and after in vivo infusion of various growth factors. Given the physiologic function of plasminogen activation in fibrinolysis, and plasminogen activators in activation of latent growth factors, the selective expression of the plasminogen activator/plasmin proteolytic cascade in oval cells expanding during liver regeneration in response to the combination of 2-AAF and partial hepatectomy, may confer a proliferative advantage to these cell populations in an extracellular matrix containing both fibrin and latent growth factors.
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PMID:Modulation of the plasminogen activator/plasmin system in rat liver regenerating by recruitment of oval cells. 952 Sep 37

The binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) has been implicated in cancer invasion and metastasis. This activity is known to be regulated by several inhibitors such as plasminogen activator inhibitors (PAIs). To elucidate the participation of the uPA system in the malignant behaviour of squamous cell carcinoma (SCC) in the oral cavity, uPA, uPAR, PAI-1 and -2 expression and localisation in 34 primary oral cancers were examined immunohistochemically. The results were then compared with clinicopathological findings. The positive rates of uPA, uPAR, PAI-1 and -2 expression were 23.5, 29.4, 29.4 and 11.8%, respectively. uPA expression correlated with mode of cancer invasion according to Yamamoto-Kohama's criteria (p < 0.01) and with secondary regional lymph node metastasis. uPAR expression also correlated with mode of invasion. In particular, the tumours of both uPA- and uPAR-positive [uPA(+)/uPAR(+)] cases were highly invasive. In the present study, neither PAI-1 nor PAI-2 expression correlated with clinicopathological parameters. However, PAI-2 negative cases of uPA(+)/uPAR(+) were significantly more invasive (p < 0.0001). Such uPA(+)/uPAR(+)/PAI-2(-) cases almost always showed secondary lymph node metastasis (p < 0.01). These results indicate that the uPA system plays a significant role in the invasive and metastatic processes of oral SCC, and that this system may be a powerful aid in evaluating the clinical course or prognosis of patients with oral cancer.
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PMID:Immunohistochemical localization of a urokinase-type plasminogen activator system in squamous cell carcinoma of the oral cavity: association with mode of invasion and lymph node metastasis. 965 21

Angiogenesis, the formation of new capillary blood vessels, is a feature of a variety of pathological processes. To study the effects of a specific group of hormones (all ligands of the steroid/retinoid/thyroid hormone receptor superfamily) on the angiogenic process in humans, we have used a model system in which human microvascular endothelial cells from foreskin (hMVEC) are cultured on top of a human fibrin matrix in the presence of basic fibroblast growth factor and tumor necrosis factor-alpha. This model mimics the in vivo situation where fibrin appears to be a common component of the matrix present at sites of chronic inflammation and tumor stroma. Our results show that testosterone and dexamethasone are strong inhibitors and all-trans retinoic acid (at-RA) and 9-cis retinoic acid (9-cis RA) are potent stimulators of the formation of capillary-like tubular structures. These effects are mediated by their respective nuclear hormone receptors as demonstrated by the use of specific synthetic receptor agonists and antagonists. 17beta-estradiol, progesterone, and 1,25-dihydroxyvitamin D3 did not affect or only weakly affected in vitro angiogenesis, which may be related to the lack of significant nuclear receptor expression. Although hMVEC express both thyroid hormone receptors alpha and beta, no effect of thyroid hormone on tube formation was found. The effects of testosterone, dexamethasone, at-RA, and 9-cis RA on tube formation were accompanied by parallel changes in urokinase-type plasminogen activator (u-PA) expression, at both mRNA and antigen levels. Exogenous suppletion of the medium with single chain u-PA enhances tube formation in our in vitro model, whereas quenching of u-PA activity (but not of tissue-type plasminogen activator activity) or of u-PA binding to u-PA receptor by specific antibodies suppressed basal and retinoid-stimulated tube formation. Moreover, addition of scu-PA to testosterone- or dexamethasone-treated hMVEC restored the suppressed angiogenic activity for a substantial part. Aprotinin, an inhibitor of plasmin activity, completely inhibited tube formation, indicating that the proteolytic properties of the u-PA/u-PA receptor complex are crucial in this process. Our results show that steroid hormones (testosterone and dexamethasone) and retinoids have strong, but opposite effects on tube formation in a human in vitro model reflecting pathological angiogenesis in the presence of fibrin and inflammatory mediators. These effects can be explained by hormone-receptor-mediated changes in u-PA expression, resulting in enhanced local proteolytic capacity of the u-PA/u-PA receptor complex.
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PMID:Effect of steroid hormones and retinoids on the formation of capillary-like tubular structures of human microvascular endothelial cells in fibrin matrices is related to urokinase expression. 968 Mar 61

In the present study, we determined the plasma and tissue concentrations of tissue-type plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2 and urokinase-type plasminogen activator receptor in 32 patients with pathology-proved gastric cancer. The plasma levels of the same markers were compared in 37 patients with benign gastric ulcer in order to find out if these plasma levels could be used to evaluate the prognostic value in patients with gastric cancer. Plasma plasminogen activator inhibitor-1 was significantly higher in gastric cancer than in benign gastric disease (p < 0.0005), whereas plasma urokinase-type plasminogen activator was significantly lower in patients with gastric cancer than in those with benign ulcer (p = 0.003). There was no significant correlation between tissue and plasma concentrations of the same parameters. The plasma and tissue levels of fibrinolytic parameters were not affected by tumor size or distant metastasis, whereas tumor tissue concentration of urokinase-type plasminogen activator receptor and plasminogen activator inhibitor-2 were significantly higher in N0 than in N1 and N2, and tissue plasminogen activator inhibitor-1 was significantly higher in N0 than in N1. Plasma levels of the five fibrinolytic parameters could not take the place of the corresponding tissue concentrations on the diagnosis and prediction of prognosis in patients with gastric cancer. Tissue concentrations of urokinase-type plasminogen activator receptor and plasminogen activator inhibitor-2, especially the latter, can be used to predict lymph node involvement in patients with gastric cancer.
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PMID:Diagnostic and prognostic values of plasma levels of fibrinolytic markers in gastric cancer. 970 Aug 49

Single-chain urokinase plasminogen activator (scuPA), the unique form secreted by cells, expresses little intrinsic plasminogen activator activity. scuPA can be activated by proteolytic cleavage to form a two-chain enzyme (tcuPA), which is susceptible to inhibition by plasminogen activator inhibitor type I (PAI-1). scuPA is also activated when it binds to its cellular receptor (uPAR), in which case the protein remains as a single chain molecule with less susceptibility to PAIs. Fibrin clots are invested with PAI-1 derived from plasma and from activated platelets. Therefore, we compared the fibrinolytic activity of complexes between scuPA and recombinant soluble uPAR (suPAR) to that of scuPA, tcuPA, and tcuPA/suPAR complexes. scuPA/suPAR complexes mediated the lysis of plasma-derived fibrin clots 14-fold more extensively than did equimolar concentrations of scuPA and threefold more extensively than did tcuPA or tcuPA/suPAR, respectively. The enhanced catalytic activity of scuPA/suPAR required that all three domains of the receptor be present, correlated with its PAI-1 resistance, was not dependent on fibrin alone, and required a plasma cofactor that was identified as IgG. Human IgG bound specifically to suPAR and scuPA/suPAR as determined by using affinity chromatography and immunoprecipitation. Plasma depleted of IgG lost most of its capacity to promote the fibrinolytic activity of scuPA/suPAR, and the activity of the complex was restored by adding plasma concentrations of purified IgG. These studies indicate that scuPA/suPAR can function as a plasminogen activator in a physiological milieu.
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PMID:Lysis of plasma clots by urokinase-soluble urokinase receptor complexes. 973 Oct 65

Endothelial cells express fibrinolytic proteins including: urokinase (u-PA) and tissue type (t-PA) plasminogen activators, type-1 (PAI-1) and 2 (PAI-2) plasminogen activator inhibitors, and u-PA receptor (u-PAR). Apoptotic endothelial cells detach, potentially forming both local and circulating microthrombi in vivo. In this article, apoptotic human umbilical vein endothelium was obtained by serum starvation and compared with nonapoptotic cells rescued from death with fresh medium containing serum. Antigen levels for t-PA, PAI-1, PAI-2, and u-PAR were reduced greatly in apoptosis (p< 0.05). In contrast, u-PA levels were similar in apoptotic as compared with rescued cells (p<0.05). Radioactive amino acids were used to determine absolute levels of protein synthesis and degradation in these cells. Reduced antigen levels likely were due to proteolysis as there was 98% total protein degradation and very little protein synthesis in apoptotic endothelial cells. Also, u-PA levels in apoptotic endothelial cells were not affected by the protein synthesis inhibitor cycloheximide. Endothelial cells in inflammatory sites are exposed to cytokines, which increase both apoptosis and u-PA levels. Data from this article support the idea that maintained u-PA levels in apoptotic endothelium may protect from micro-thrombosis in inflammatory sites as well as in the circulation.
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PMID:Fibrinolytic proteins in apoptotic human umbilical vein endothelial cells. 975 33

The plasminogen activator system is known to play a crucial role in the angiogenesis process by modulating the adhesive properties of endothelial cells to the extracellular matrix and cell-cell interaction. In the present study, we demonstrated that the urokinase-type plasminogen activator (u-PA) induced neovascular growth in the avascular rabbit cornea and dose-dependently promoted growth, chemotaxis, and matrix invasion of cultured endothelial cells. Interaction between u-PA and its receptor appears to be mandatory for the angiogenic effect of u-PA because monoclonal antibodies anti-u-PA and anti-u-PA receptor (u-PAR) blocked the proangiogenic effects of u-PA at the endothelial cell level. We then assessed the signaling pathway activated in endothelial cells by u-PA. u-PAR activation by u-PA produced de novo synthesis of diacylglycerol (DAG) from glucose by a cytochalasin B-inhibitable mechanism, indicating the involvement of a specific glucose transporter (GLUT). Endothelial cells expressed GLUT2, whose activation was tyrosine kinase-dependent and protein kinase C (PKC)-independent. The increase of glucose uptake led to DAG production, which resulted in PKC activation/translocation. Impairment of u-PAR availability by monoclonal antibodies and by antisense oligonucleotides (aODN) against u-PAR mRNA inhibited glucose uptake, DAG neosynthesis, and PKC activation, resulting in the blockade of endothelial cell proliferation, chemotaxis, and chemoinvasion. These data suggest that u-PAR activation consequent to the binding of u-PA can be regarded as an "angiogenic switch" and disclose the possibility that an anti-u-PAR aODN strategy may efficiently target endothelial cell function to control angiogenesis in vivo.
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PMID:Urokinase-dependent angiogenesis in vitro and diacylglycerol production are blocked by antisense oligonucleotides against the urokinase receptor. 975 55

The tissue concentrations of urokinase-type plasminogen activator (u-PA), urokinase-type plasminogen activator receptor (u-PAR), plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were investigated by an ELISA technique in normal and malignant samples of the prostate from 24 patients undergoing radical prostatectomy for organ-confined prostate cancer. The median concentration of u-PA was significantly higher in cancerous than in normal prostate tissue (p = 0.006). No significant increase of u-PAR, PAI-1 and t-PA was found in cancer tissue in comparison with the benign samples (p > 0.05). Assessment of the relationship between fibrinolytic proteins and DNA ploidy revealed an increased u-PA, u-PAR and PAI-1 in diploid prostate cancer as compared with the normal controls. However, in aneuploid cancer u-PA remained high but u-PAR and PAI-1 were decreased. This led to a higher local concentration of u-PA in aneuploid samples than in normal prostate and in diploid prostate cancer. No alteration of median t-PA was found in benign prostate or in diploid or aneuploid prostate cancer. The altered expression of u-PA, u-PAR and PAI-1 in diploid and aneuploid prostate cancer suggests a possible role of fibrinolytic proteins in the different biologic behavior of tumors, and may be one explanation for the higher metastatic potential of aneuploid tumors.
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PMID:Analysis of fibrinolytic proteins in relation to DNA ploidy in prostate cancer. 976 66

Overexpression of tissue factor (TF) is characteristically observed in advanced pancreatic cancer and has been associated with invasion and metastasis. Functional responses of TF activation are here investigated using as a model system the human pancreatic cancer cell lines SW979 (which overexpresses TF) and MIAPaCa2 (which does not express detectable levels). After stimulation of these cell lines with factor VIIa (FVIIa), the only known TF ligand, expression of urokinase receptor (uPAR) gene was up-regulated in SW979 cells in a dose-dependent manner but not in MIAPaCa2 cells. Interestingly, urokinase (uPA) and its specific inhibitor PAI-1 were not up-regulated. Exposure to functionally inactivated FVIIa did not show any effect on uPAR expression on SW979 cells despite binding to TF with higher efficiency. The neutralizing anti-TF antibody 5G9 blocked the FVIIa-induced up-regulation of uPAR completely, whereas hirudin failed to block this up-regulation. Treatment of SW979 cells with Factor Xa did not up-regulate the expression of uPAR gene, whereas treatment with FVII induced the same level of enhanced uPAR gene expression as that with FVIIa. In the matrigel invasion assay, enhanced invasion of SW979 cell line induced by FVIIa was completely inhibited by anti-TF antibody and alpha2-antiplasmin. Moreover, the endogenous levels of uPAR gene expression were significantly correlated with the level of TF gene expression in 19 human cancer cell lines (P < 0.05). These data suggest that up-regulation of uPAR expression by tumor cells leading to tumor invasion is induced through the TF-FVIIa pathway rather than TF-initiated thrombin generation. This is the first report that TF may be one of the key receptors that can up-regulate expression of the plasminogen activator receptor in human cancer cells to enhance tumor invasion and metastasis.
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PMID:Enhanced expression of urokinase receptor induced through the tissue factor-factor VIIa pathway in human pancreatic cancer. 976 79


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