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)

The GPI-anchored urokinase plasminogen activator receptor (uPAR) does not internalize free urokinase (uPA) but readily internalizes and degrades uPA:serpin complexes in a process that requires the alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha2MR-LRP). This process is accompanied by the internalization of uPAR which renders it resistant to phosphatidylinositol-specific phospholipase C (PI-PLC). In this paper we show that during internalization of uPA:serpins at 37 degrees C, analysed by FACScan, immunofluorescence and immunoelectron microscopy, an initial decrease of cell surface uPAR was observed, followed by its reappearance at later times. This effect was not due to redistribution of previously intracellular receptors, nor to the surface expression of newly synthesized uPAR. Recycling was directly demonstrated in cell surface-biotinylated, uPA:PAI-1-exposed cells in which biotinylated uPAR was first internalized and subsequently recycled back to the surface upon incubation at 37 degrees C. In fact, uPAR was resistant to PI-PLC after the 4 degrees C binding of uPA:PAI-1 to biotinylated cells, but upon incubation at 37 degrees C PI-PLC-sensitive biotinylated uPAR reappeared at the cell surface. Binding of uPA:PAI-1 by uPAR, while essential to initiate the whole process, was, however, dispensable at later stages as both internalization and recycling of uPAR could be observed also after dissociation of the bound ligand from the cell surface.
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PMID:Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. 918 8

The plasminogen activation (PA) system plays an important role in tumor invasion by initiating pericellular proteolysis of the extracellular matrix (ECM) and inducing cell migration. Malignant brain tumors overexpress PA members and characteristically invade by migrating on ECM-producing white matter tracts and blood vessel walls. To determine whether urokinase-type plasminogen activator (uPA) and its receptor (uPAR) directly modulate the migration of brain tumor cells, we examined six human brain tumor cell lines, 2 astrocytomas (SW1088, SW1783), 2 medullobastomas (Daoy, D341Med), and 2 glioblastomas (U87MG, U118MG), for their surface uPAR expression, endogenous PA activity, and functional proteolytic activity by an ECM-degradation assay. Migration on Transwell membranes and invasion of Matrigel was then tested by pre-incubating the cells with increasing concentrations of either uPA, the proteolytically inactive amino-terminal fragment (ATF) of uPA, or the uPAR cleaving enzyme, phosphatidylinositol-specific phospholipase C (PI-PLC). All of the cell lines, except D341Med, express surface uPAR protein and uPA activity. High levels of uPAR and uPA activity correlated with cellular degradation of ECM, cell migration, and Matrigel invasion. Cell migration and invasion were enhanced by uPA or ATF in a dose dependent manner, while PI-PLC treatment abolished the uPA effect and inhibited migration and invasion. We conclude that ligation of uPAR by uPA directly induces brain tumor cell migration, independent of uPA-mediated proteolysis; and in concert with ECM degradation, markedly enhances invasion. Conversely, removing membrane bound uPAR from the surface of the cells studied inhibited their ability to migrate and invade even in the presence of proteolytically active uPA.
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PMID:Urokinase induces receptor mediated brain tumor cell migration and invasion. 1006 93

We showed previously that pemphigus IgG enhanced both the activity of urokinase plasminogen activator (uPA) in cultured cells and the expression of its receptor (uPAR) on uPA-binding keratinocytes. In the present study, to clarify whether uPAR and uPA-activated plasmin are actually involved in the blistering process after pemphigus IgG binding to the cell surface, we examined the effects of the following on uPAR expression and on cell-cell detachment in DJM-1 cells, a squamous cell carcinoma line: (i) phosphatidylinositol-specific phospholipase C (PI-PLC) - which releases uPAR from the membrane surface into the culture medium by cleaving the glycosylphosphatidylinositol anchor thus inhibiting uPAR activity, and (ii) uPA inhibitors (tranexamic acid, aprotinin, p-aminobenzonic acid and dexamethasone). Preincubation with PI-PLC decreased dramatically the pemphigus IgG-induced uPAR expression in a dose-dependent manner, and inhibited pemphigus IgG-induced cell-cell detachment at 10 microg/mL. On the other hand, tranexamic acid (15 mM) inhibited pemphigus IgG-induced cell-cell detachment without reduction of uPAR expression, although aprotinin, p-aminobenzonic acid and dexamethasone failed to alter either of these parameters. Although uPAR expression on the pemphigus IgG-bound cell surface and uPA activation may contribute significantly to the pathogenesis of acantholysis in pemphigus, the mechanisms are complicated and should be defined further.
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PMID:Phosphatidylinositol-specific-phospholipase C cleaves urokinase plasminogen activator receptor from the cell surface and leads to inhibition of pemphigus-IgG-induced acantholysis in DJM-1 cells, a squamous cell carcinoma line. 1142 78

Tumor cell motility and invasion have been linked to upregulated signaling from both the epidermal growth factor receptor (EGFR) and that for urokinase-type plasminogen activator (uPAR). However, we do not know whether these events are interdependent or unrelated, despite the obvious diagnostic and therapeutic implications. Gene microarray analyses have suggested that EGFR signaling via phospholipase C-gamma (PLCgamma) induces uPAR transcription. We utilized two sublines of the DU145 human prostate carcinoma cell line that are genetically engineered to differentially activate the EGFR/PLCgamma cascade and are variously invasive in vitro and in vivo. uPAR protein levels in these cells were found to be dependent on PLC signaling, pharmacologic inhibition of PLC signaling reduced uPAR expression. To determine whether uPAR was a required element in EGFR-mediated invasion, we stably expressed uPAR cDNA in either sense or antisense orientation in the two DU145 sublines. Interestingly, uPA production was modulated in parallel, although to a lesser degree, with uPAR in these sublines. Antisense to uPAR significantly restricted invasion of the highly invasive DU145 WT cells through Matrigel and reduced aggressiveness of tumors in nude mice. Up-regulation of uPAR significantly increased the invasiveness of the moderately invasive DU145 parental (DU145 P) cells through Matrigel, but this increased invasiveness was not seen in mice. uPA activity appears to contribute to invasiveness at least through Matrigel, as antibody to uPA or amiloride limited the transmigration. These results support a model of tumor invasion promoted by autocrine EGFR signaling involving reinforcing altered gene expression, of uPAR at least, that further induces cell motility. Herein, a number of key molecules whose expression levels are interrelated, including both EGFR and uPAR, are required but none are sufficient in the absence of other keys molecules in promoting tumor progression.
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PMID:DU145 human prostate carcinoma invasiveness is modulated by urokinase receptor (uPAR) downstream of epidermal growth factor receptor (EGFR) signaling. 1530 76

Protein kinase C (PKC) superfamily play key regulatory roles on the development of cancer. However, the exact role of these enzymes in human hepatocellular carcinoma (HCC) has not been well established. Using the RT-PCR and Western blotting to analyze the levels of PKC isoforms mRNA and protein in the five different differentiated hepatoma cell lines, we found that PKC alpha was highly expressed in the poor-differentiated HCC cell lines (SK-Hep-1 and HA22T/VGH) as compared with that in the well-differentiated HCC cell lines (PLC/PRF/5, Hep3B, and HepG2). When treated with PKC alpha antisense oligonucleotides (ODN), both HA22T/VGH and SK-Hep-1 cells lines showed the reduction of PKC alpha expression, as well as a deceleration in the growth rate and in the level of cyclin D1, but the increase in the levels of p53 and p21(WAF1/CIP1). Moreover, the reduction of PKC alpha expression also inhibited the migratory and invasive potential of both HA22T/VGH and SK-Hep-1 cells lines, and revealed a down-regulation of several migration/invasion-related genes (MMP-1, u-PA, u-PAR, and FAK). These phenomenon were also confirmed by DNA-based small interfering RNA (siRNA) PKC alpha and PKC alpha/beta specific inhibitor Go6976. Thus, the results indicated that PKC alpha may be associated with regulation of cell proliferation/migration/invasion in human poorly differentiated HCC cells, suggesting a role for the PKC alpha in the malignant progression of human HCC.
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PMID:Reduction of PKC alpha decreases cell proliferation, migration, and invasion of human malignant hepatocellular carcinoma. 1748 87

The fibrinolytic function of endothelial cells plays an important role in the pathophysiology of pulmonary vascular diseases. In this study, the effects of pro-urokinase, a new thrombolytic drug that is currently being tested for the treatment of pulmonary embolism, on the expression of urokinase-type plasminogen activator (u-PA) and u-PA receptor (u-PAR) were assessed. The role of u-PAR was also investigated. Immunocytofluorescence and RT-PCR techniques were employed. In normal human pulmonary arterial endothelial cells (HPAECs), the expression levels of u-PA and u-PAR were very low. Incubation with pro-urokinase up-regulated u-PA expression at both the mRNA level and the protein level; however, the expression of u-PAR was not affected. The effect of pro-urokinase induction was totally inhibited by the release of u-PAR from the HPAECs' surface with PLC. This result suggests that the combination of u-PA with u-PAR may be a critical pathway for the induction of u-PA expression.
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PMID:Pro-urokinase up-regulates the expression of urokinase-type plasminogen activator (u-PA) in human pulmonary arterial endothelial cells. 1764 Jul 19

Osteopontin (OPN, SPP1) is a secretory extracellular matrix protein that has been implicated in cancer-associated mechanisms such as metastasis, invasion and angiogenesis. Three OPN isoforms (OPN-a, -b and -c) derived from alternative splicing are known to exist, but their functional specificity remains unclear. Here, we found that the expression profile of OPN isoforms in hepatocellular carcinoma (HCC) cell lines and patient tissues were correlated with specific cellular phenotypes and tumorigenicity of HCC. Thus, SK-Hep1 cells with a robust migratory capacity dominantly expressed both OPN-a and -b, but non-migratory cell lines such as Hep3B and PLC/PRF/5 mainly expressed OPN-c. Moreover, tumor tissues predominantly expressed OPN-a and -b, whereas normal liver tissues mainly expressed OPN-c. Transwell infiltration and wound-induced migration assays revealed that both OPN-a and -b induced Hep3B cell migration, while OPN-c had no significant effects. By contrast, OPN-c suppressed the migratory activity of SK-Hep1 cells although no significant changes were induced by OPN-a. Consistently, OPN isoforms differentially activated migration-associated signaling pathways such that OPN-a and -b increased the expression of urokinase type plasminogen activator and the phosphorylation of p42/p44 MAP kinase, but these pathways were not activated by OPN-c. Thus, the findings of the present study suggest that OPN splice variants differentially couple to signaling pathways to modulate the migratory property of HCC cells and that this is one of the mechanisms underlying the pathological heterogeneity of HCC progression.
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PMID:Osteopontin splice variants differentially modulate the migratory activity of hepatocellular carcinoma cell lines. 1988 63