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)

Many cancer cell lines and cancers overexpress receptor bound urokinase plasminogen activator on the cell surface. The urokinase plasminogen activator bound to its receptor remains on the cell surface for a prolonged period of time. When urokinase plasminogen activator/urokinase plasminogen activator receptor complex binds plasminogen activator inhibitor (PAI-1), the inhibitor triggers a series of events leading to internalization of the entire complex. This mechanism makes a very attractive target for localization and internalization of PAI-1-based cytotoxic compounds in cancer treatment. We investigated the antitumor activity of PAI-1/A-chain cholera toxin in vitro. Fibrosarcoma-derived HT1080 cells treated with PAI-1 conjugate showed at least 4 times higher cell killing than the control KD normal fibroblast cell line.
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PMID:Antitumor activity of the type 1 plasminogen activator inhibitor and cytotoxic conjugate in vitro. 132 17

A truncated version of the human urokinase plasminogen activator receptor has been obtained by in vitro mutagenesis by insertion of a premature nonsense codon in the urokinase plasminogen activator receptor cDNA. This results in a protein truncated immediately upstream of the region which appears to be required for membrane attachment of the receptor via a glycolipid anchor. The modified receptor cDNA inserted into an expression vector has been transfected into mouse LB6 cells. Transfectants produce a urokinase plasminogen activator (u-PA)-binding protein that is secreted into the medium. It can be cross-linked to iodinated ATF (amino-terminal fragment of u-PA) and can also inhibit binding of iodinated ATF to mouse LB6 cells that express the wild type human receptor. The soluble u-PA receptor will be used in a variety of experiments aimed at identifying the role and mechanism of u-PA in physiological and pathological invasive processes, as well as in therapeutical attempts to block or decrease cancer cell invasion and in general u-PA-mediated tissue destruction.
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PMID:A soluble, ligand binding mutant of the human urokinase plasminogen activator receptor. 185 Nov 52

Integrin alpha v beta 3 is a marker of progression in malignant melanoma. Previously we reported that human melanoma cells derived from regional lymph node metastases had increased alpha v beta 3-mediated adhesion to lymph node vitronectin. In the present study, the expression and function of alpha v beta 3 were further investigated with emphasis on the functional relationship between alpha v beta 3 and the urokinase-type plasminogen activator system of proteolysis. We found that metastases-derived melanoma MeWo LNI 6I (6I) and MIM/8 LNI cells had a markedly increased expression of alpha v mRNA transcripts relative to the parent lines which was reflected in significantly elevated levels of the alpha v beta 3 heterodimers on the cell surface. These cells also expressed elevated levels of urokinase plasminogen activator receptor (uPAR) mRNA and had higher levels of surface bound urokinase plasminogen activator as detected by immunolabeling. To determine whether the expression of uPAR and alpha v were linked, alpha v synthesis in the metastatic melanoma cells was suppressed using alpha v antisense phosphorothioate oligonucleotides. This resulted in a marked decrease in detectable alpha v mRNA and protein and a corresponding substratum-specific reduction in cell adhesion to vitronectin. When uPAR expression in these cells was subsequently analyzed, we found a reduction of approximately 50% in uPAR mRNA levels. On the other hand, ligation of the alpha v beta 3 receptor on the melanoma cells by immobilized antibody resulted in a twofold increase in uPAR mRNA. The results suggest that the expression of uPAR in metastatic melanoma cells is linked to the expression and function of the vitronectin receptor.
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PMID:Coordinated expression of the vitronectin receptor and the urokinase-type plasminogen activator receptor in metastatic melanoma cells. 753 55

The biosynthesis and the surface localization of the urokinase plasminogen activator receptor (uPAR) were analysed in MDCK epithelial cells and in unpolarized fibroblasts. No differences were observed with respect to rate of synthesis, nature of precursors and time of surface appearance. uPAR was localized particularly at the focal and cell-cell contacts when expressed in fibroblasts. On the contrary, in MDCK cells uPAR was found mostly on the apical surface; in agreement with its localization, down-regulation of uPAR by the uPA-PAI-1 complex was observed only from the apical membrane.
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PMID:Biosynthesis and apical localization of the urokinase receptor in polarized MDCK epithelial cells. 764 59

The urokinase plasminogen activator receptor (uPAR), a glycosylphosphatidylinositol-linked glycoprotein, plays a central role in the regulation of pericellular proteolysis and participates in events leading to cell activation. Here, we demonstrate that uPAR, on a human melanoma cell line, is localized in caveolae, flask-shaped microinvaginations of the plasma membrane found in a variety of cell types. Indirect immunofluorescence with anti-uPAR antibodies on the melanoma cells showed a punctated staining pattern that accumulated to stretches along sides of cell-cell contact and membrane ruffles. uPAR colocalized with caveolin, a characteristic protein in the coat of caveolae, as demonstrated by double staining with specific antibodies. Further, uPAR could be directly localized in caveolae by in vivo immunoelectron microscopy. Both uPAR and its ligand, uPA, were present in caveolae enriched low density Triton X-100 insoluble complexes, as shown by immunoblotting. From such complexes, caveolin could be coprecipitated with uPAR-specific antibodies suggesting a close spatial association between uPAR and caveolin that might have implications for the signal transduction mediated by uPAR. Further, functional studies indicated that the localization of uPAR and its ligand in caveolae enhances pericellular plasminogen activation, since treatment of the cells with drugs that interfere with the structural integrity of caveolae, such as nystatin, markedly reduced cell surface plasmin generation. Thus, caveolae promote efficient cell surface plasminogen activation by clustering uPAR, uPA, and possibly other protease receptors in one membrane compartment.
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PMID:The urokinase-type plasminogen activator receptor, a GPI-linked protein, is localized in caveolae. 772 38

Radiolabeled pro-urokinase plasminogen activator (pro-uPA) was cross-linked to a specific protein on the surface of human monocyte-like U937 cells in a reaction catalyzed by tissue transglutaminase. The conjugate formed with this unknown component had a much higher molecular weight (apparent M(r) 250,000-300,000) than the complex of pro-uPA and the urokinase plasminogen activator receptor (uPAR). There was a strong preference for the pro-form of uPA. The conjugate was recognized by antibodies against uPA but not by anti-uPAR antibodies. Nevertheless, the blocking of uPAR with a monoclonal antibody abolished the formation of the conjugate, thus showing a role of uPAR in this process.
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PMID:A novel, specific pro-urokinase complex on monocyte-like cells, detected by transglutaminase-catalyzed cross-linking. 790 48

Current evidence regarding the regulation of urokinase-dependent extracellular proteolysis indicates that plasminogen activation is a surface-associated process. We have compared the histological localization of urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) in breast cancer sections using a panel of monoclonal antibodies. First, the ability of six different anti-uPA monoclonal antibodies to recognize pro-uPA, uPA, and in vitro-formed complexes of uPA with either soluble uPAR or with plasminogen activator inhibitor type 1 was compared. Then the reactivity of the anti-uPAR antibodies was tested, and the occurrence of an uPA receptor of about M(r) 55,000 in samples from breast carcinoma was assessed by immunoprecipitating the uPA receptor from an in vitro 125I-labeled tumor extract. Immunocytochemical data from adjacent sections of 10 tumor specimens showed that antibodies recognizing free and bound uPA mostly stain the cytoplasm and the membrane of epithelial tumor cells in confined areas of the tumor and some fibroblast-like stromal cells. Acid pretreatment of tumor sections, which removes receptor-bound uPA, causes a strong reduction of the immunocytochemical reactivity of epithelial tumor cells, whereas staining of fibroblast-like cells is not considerably affected. Consistent with these results, epithelial tumor cells were mostly unreactive to anti-uPAR antibodies unless pretreated with acidic buffer, whereas fibroblast-like stromal cells showed a faint but acid-resistant staining with all anti-uPARs. In conclusion, these results show that occupied uPA receptors are definitely present on the membrane of epithelial tumor cells and suggest the occurrence of uPA-uPAR-dependent proteolytic activity on the surface of breast cancer cells.
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PMID:Tissue distribution of soluble and receptor-bound urokinase in human breast cancer using a panel of monoclonal antibodies. 792 78

Activation of the proenzyme of urokinase (uPA) on the surface of cancer cells has been implicated in the initiation of focal proteolytic mechanisms that permit invasion and metastasis by colon cancers. The activity of uPA on the cell surface appears to be a function of the number of uPA-specific receptors (uPAR) and the extent of inhibition of uPA by plasminogen activator inhibitors (PAI). The mapping of the genes coding for uPAR, and for PAI-2, was performed to determine whether their chromosomal localization suggested their involvement in the genetic alterations associated with cancer cell DNA. This study confirms the localization of the human urokinase plasminogen activator receptor gene to chromosome 19q and, using in situ hybridization, provides a precise localization to chromosome 19q13.2. In addition, our results confirm the previous allocation of the human plasminogen activator inhibitor-2 gene to a location 18q21.3-->18q22.1, a location that corresponds to the commonest (> 70%) somatic deletions found in colorectal carcinomas. The mapping of the uPAR and PAI-2 genes enables the elucidation of their possible involvement in the genetic alterations that determine the invasive and metastatic phenotypes in colorectal cancer.
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PMID:Chromosomal localization of the human urokinase plasminogen activator receptor and plasminogen activator inhibitor type-2 genes: implications in colorectal cancer. 794 15

The malignant potential of solid tumors is related to the ability to invade adjacent tissue and to metastasize. These properties of cancer cells depend on the synthesis of proteolytic enzymes which are able to digest adjacent connective tissue and basement membranes. We hypothesized that all elements of the plasminogen activation system might be overexpressed in malignant human breast tumors, functioning as an essential element in tumor invasion and metastasis. As determined by histopathological methods, the malignant tumors showed statistically significantly higher expression of urokinase plasminogen activator (uPA), type-1 plasminogen activator inhibitor (PAI-1), and especially urokinase plasminogen activator receptor (uPAR) than benign tissues. All those elements were present in higher amounts in the cancer cells than in the cells of benign or normal breast tissues. High exhibition of tissue plasminogen activator (tPA) found in cancer seems to be random and not related to the malignant or benign state, since benign and malignant tumors show overexpression of tissue plasminogen activator with similar frequency. When the tumors express high amounts of uPA, they express a high amount of uPAR in 50% of cases and PAI-1 in 57.3% of cases. When urokinase is expressed in low amount, the receptor is low in 28.6% and inhibitor in 21.4% of malignant breast tumors. This statistically significant consensus, 78.6% in the case of urokinase and its receptor and 78.6% in case of urokinase and its inhibitor, suggests that these activities may be the result of a unique mechanism of control, activated in the last steps of malignant transformation.
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PMID:Expression and localization of elements of the plasminogen activation system in benign breast disease and breast cancers. 822 86

Although the mechanisms governing EC activation are not well understood, evidence points to a role for locally released cytokines from activated leukocytes. We propose that the sequence of events that result in EC activation are important in perivascular leukocyte infiltration into the CNS seen in MS. In the present study we examined expression of EC activation antigens on cerebral microvessels from patients with MS using immunofluorescence staining and quantitation by laser cytometry. Normal human microvessels do not express MHC class II antigens (Ags), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), or the urokinase plasminogen activator receptor (uPA-R). They express low levels of transferrin receptors and express factor VIII. Microvessels prepared from MS brain with plaque involvement expressed decreased factor VIII and increased transferrin receptors (tfR). Expression of the adhesion molecules VCAM-1, and ICAM-1 were found on 80% of isolated microvessels. HLA-DR Ags were expressed on 40-60% of microvessels, and the uPA-R was expressed on 50% of MS microvessels examined. MHC class II Ags co-express with VCAM-1 and ICAM-1 more frequently than with the uPA-R. Results indicate that activation of EC in MS is likely to be an important factor in disease pathology.
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PMID:Expression of endothelial cell activation antigens in microvessels from patients with multiple sclerosis. 833 39


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