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1
Poláková, Markéta. "Draci a hrdinové – upíři a oběti (hledání magických bytostí ve světě vědy a techniky)." Anthropologia integra 2, no. 2 (June 1, 2011): 53–61. http://dx.doi.org/10.5817/ai2011-2-53.
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Tématem tohoto příspěvku je analýza hledání magických bytostí draků a upírů v postmoderním světě vědy a techniky. Na první pohled se může zdát, že tyto bytosti, tak vzdálené od racionalismu dnešní doby, nemohou nalézt své reálné vyjádření. Cílem této studie je popsat, jakým způsobem se příběhy o monstrech, jejich obětech a hrdinech, které je přicházejí zachránit, přizpůsobily kulturnímu kódu dnešní doby. Nakolik si draci a upíři uchovali svou původní identitu a nakolik se rozdíly mezi hrdinou a monstrem začaly stírat? Zvláštní pozornost je věnovaná fenoménu role playing games a dnešní podobě literárního upíra, přičemž jsou zde zohledněny i genderové rozdíly v přístupu k těmto fantastickým bytostem.
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Uhrin, Pavel, and Johannes M. Breuss. "uPAR." Cell Adhesion & Migration 7, no. 1 (January 2013): 23–26. http://dx.doi.org/10.4161/cam.22124.
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Muradova, Nargiz A., Rayiha B. Amenzade, and Rustam B. Rustamov. "Architectural Design in Town Planning with Use of Advances of Space Technology." Urban Planning and Design Research 3 (2015): 1. http://dx.doi.org/10.14355/updr.2015.03.001.
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Nagasawa, Ryota, Asuka Fukushima, Lissa Fajri Yayusman, and Dandy Aditya Novresiandi. "Urban Expansion and Its Influences on The Suburban Land Use Change in Jakarta Metropolitan Region (JABODETABEK)." Urban Planning and Design Research 3 (2015): 7. http://dx.doi.org/10.14355/updr.2015.03.002.
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Triantakonstantis, Dimitrios, Nektarios Chrysoulakis, Anna Sazonova, Thomas Esch, Christian Feigenwinter, Sebnem Düzgün, Ebwerhard Parlow, Mattia Marconcini, and Abraham Tal. "On-line Εvaluation of Earth Observation Derived Indicators for Urban Planning and Management." Urban Planning and Design Research 3 (2015): 17. http://dx.doi.org/10.14355/updr.2015.03.003.
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Qiao, Fengxiang, Ling Liu, Long Wen, Qing Li, and Lei Yu. "Characterizing the Relationships between Real Estate Values and Communizing Time: a Case Study in Texas Suburban Cities." Urban Planning and Design Research 4 (2016): 1. http://dx.doi.org/10.14355/updr.2016.04.001.
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Serrano-Arellano, J., M. Davila-Nuñez, J. M. Belman-Flores, K. Aguilar-Castro, E. V. Macias-Melo, J. C. Rodriguez-Uribe, and Z. B. Trejo-Torres. "The Influence of Climate on Rural Housing: Thermal Bioclimatic Elements and "Psycho-Thermal-Stress"." Urban Planning and Design Research 5 (2017): 1. http://dx.doi.org/10.14355/updr.2017.05.001.
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Lippert, Solvej, Kasper Drimer Berg, Peter Iversen, Gunilla Høyer-Hansen, Ib Jarle Christensen, Klaus Brasso, and M. Andreas Røder. "Urokinase plasminogen activator receptor (uPAR) as a novel biomarker in prostate cancer." Journal of Clinical Oncology 33, no. 7_suppl (March 1, 2015): 183. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.183.
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183 Background: New biomarkers are warranted to distinguish between indolent and aggressive prostate cancer (PCa). The urokinase plasminogen activator receptor (uPAR) plays an important role in pericellular proteolysis by binding urokinase plasminogen activator (uPA). This is required for degradation of the extracellular matrix and for cancer invasion. In addition to binding uPAR, uPA cleaves uPAR liberating uPAR(I) and uPAR(II-III). Intact, uPAR(I-III), and uPAR(II-III) can be liberated from the cell surface resulting in three different uPAR forms in circulation. The different uPAR forms are strong prognostic markers in several cancers. We measured the uPAR forms in plasma from patients with different stages of PCa. Methods: Between February 1, 2012 and October 1, 2014, 400 patients with PCa (se table) had plasma samples obtained. The levels of intact uPAR [uPAR(I-III)], intact uPAR + cleaved uPAR domains II+III [uPAR(I-III) + uPAR(II-III)], and cleaved uPAR domain I [uPAR(I)] were determined in citrated plasma samples with two-site sandwich time-resolved fluorescence immunoassays (TR-FIAs). Results: Plasma uPAR(I-III) + uPAR(II-III) and uPAR(I) were significantly higher in hormone naïve patients and CRPC patients compared to patients with localized disease (see table). Quantification of intact uPAR(I-III) revealed no significant differences between the three groups. Conclusions: Our findings suggest that uPAR(I-III) + uPAR(II-III) and uPAR(I) are associated with higher tumor stage as well as advanced PCa disease. These associations suggest that uPAR domains in plasma harbour prognostic value for PCa patients. Further studies are warranted to validate the use of uPAR forms as biomarkers for PCa. [Table: see text]
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Huang, M., Q. Huai, A. Zhou, A. Mazar, G. Parry, A. Kuo, D. Cines, Y. Li, B. Furie, and B. C. Furie. "ID: 86 Structural basis of uPAR-uPA and uPAR-vitronectin interactions." Journal of Thrombosis and Haemostasis 4, s1 (October 2006): 227. http://dx.doi.org/10.1111/j.1538-7836.2006.00086.x.
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Gorrasi, Anna, Anna Maria Petrone, Anna Li Santi, Mariaevelina Alfieri, Nunzia Montuori, and Pia Ragno. "New Pieces in the Puzzle of uPAR Role in Cell Migration Mechanisms." Cells 9, no. 12 (November 24, 2020): 2531. http://dx.doi.org/10.3390/cells9122531.
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The urokinase (uPA) receptor (uPAR) plays a key role in cell migration. We previously showed that uPAR-negative HEK-293 cells efficiently migrate toward serum but, after uPAR ectopic expression, migrate only in a uPAR-dependent manner. In fact, migration of uPAR-transfected HEK-293 (uPAR-293) cells is impaired by anti-uPAR antibodies, without recovery of the uPAR-independent migration mechanisms formerly active. Prostate carcinoma PC3 cells, which express high endogenous uPAR levels, migrated only through a uPAR-dependent mechanism; in fact, the silencing of uPAR expression inhibited their migration. We hypothesize a crucial role of the uPAR glycosyl-phosphatidyl-inositol (GPI) tail, which promotes uPAR partitioning to lipid rafts, in uPAR-controlled cell migration. Here, we show that removal of the uPAR GPI-tail, or lipid rafts disruption by methyl-beta-cyclodextrin impairs migration of PC3 cells, incapable of uPAR-independent migration, whereas it restores uPAR-independent migration in uPAR-293 cells. We then show that, in PC3 cells, both uPAR signaling partners, β1 integrins and receptors for formylated peptides (FPRs), partly associate with lipid rafts. Inhibition of their interaction with uPAR impairs this association and impairs cell migration. Interestingly, blocking uPAR association with FPRs also impairs β1 integrin partitioning to lipid rafts, whereas blocking its association with β1 integrins has no effect on FPRs partitioning. On these bases, we propose that uPAR controls cell migration by connecting β1 integrins and FPRs and, through its GPI tail, by driving them into lipid rafts, thus promoting pro-migratory signals. uPAR-mediated partitioning of integrins to lipid rafts is strictly dependent on uPAR association with FPRs.
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Park, Young-Jun, Gang Liu, Yuko Tsuruta, Emmanuel Lorne, and Edward Abraham. "Participation of the urokinase receptor in neutrophil efferocytosis." Blood 114, no. 4 (July 23, 2009): 860–70. http://dx.doi.org/10.1182/blood-2008-12-193524.
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AbstractThe urokinase receptor (uPAR) plays an important role in regulation of fibronolysis, cell migration, and adhesion. In this study, we examined whether uPAR plays a role in modulating efferocytosis of neutrophils. Macrophages from uPAR−/− mice demonstrated enhanced ability to engulf viable wild-type (WT) neutrophils in vitro and in vivo in the lungs. The increased phagocytic activity of uPAR−/− macrophages was abrogated by incubation with soluble uPAR (suPAR), arginine-glycine-aspartic acid (RGD)–containing peptides, or anti-integrin antibodies. There was increased uptake of viable uPAR−/− neutrophils by WT macrophages. Incubation of uPAR−/− neutrophils with suPAR or anti-integrin antibodies diminished uptake by WT macrophages to baseline. Uptake of uPAR−/− neutrophils by uPAR−/− macrophages was not enhanced. However, incubation of uPAR−/− neutrophils or uPAR−/− macrophages, but not both, with suPAR enhanced the uptake of viable uPAR−/− neutrophils by uPAR−/− macrophages. The adhesion of WT neutrophils to uPAR−/− macrophages was higher than to WT macrophages. uPAR−/− neutrophils demonstrated increased adhesion to suPAR, which was abrogated by blocking of low-density lipoprotein related protein and integrins. Expression of uPAR on the surface of apoptotic neutrophils was reduced compared with levels on viable neutrophils. These results demonstrate a novel role for uPAR in modulating recognition and clearance of neutrophils.
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Kotzsch, Matthias, Axel Meye, Thomaz Langerholc, Susanne Füssel, Natalie Olbricht, Sybille Albrecht, Detlev Ockert, et al. "Identification of a novel urokinase receptor splice variant and its prognostic relevance in breast cancer." Thrombosis and Haemostasis 89, no. 04 (2003): 705–17. http://dx.doi.org/10.1055/s-0037-1613577.
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SummaryThe cellular receptor for urokinase-type plasminogen activator, uPAR, plays a central role in both cell surface-associated proteolysis and cellular adhesion. In the present study, we systematically searched for splice variants of uPAR mRNA in human cells and tumor tissues by qualitative RT-PCR using specific primers for uPAR exons 1 and 6. Beside the wild-type (wt) uPAR mRNA and the previously described splice variant lacking exon 5 (uPAR-del5), a novel splice variant lacking both exons 4 and 5 (uPAR-del4/5) was found predominantly in various cancer cell lines. To elucidate whether alternatively spliced uPAR mRNA may be translated and post-translationally processed, we generated stably transfected Chinese hamster ovary cells, which harbor expression plasmids of wt uPAR and various uPAR variants including uPAR-del5 and uPAR-del4/5. By ELISA, flow cytofluorometry, and Western blot analysis, we confirmed synthesis and secretion of wt uPAR and the uPAR variants by the use of domain-specific monoclonal antibodies against uPAR. For quantification of uPAR mRNA variants, we established two highly sensitive real-time RT-PCR assays based on LightCycler technology. Study of their expression in a representative set of breast cancer tissues indicated that the novel mRNA variant uPAR-del4/5 was expressed very frequently and independently of uPAR mRNA variants covering exon 4 (uPAR-wt and uPAR-del5). Higher uPAR-del4/5 expression was significantly associated with shorter disease-free survival (p = 0.0004) of breast cancer patients. These results suggest that uPAR-del4/5 mRNA may serve as a novel prognostic marker in breast cancer.Theme paper: Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.
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Alfano, D., P. Ragno, M. P. Stoppelli, and A. J. Ridley. "RhoB regulates uPAR signalling." Journal of Cell Science 125, no. 10 (February 24, 2012): 2369–80. http://dx.doi.org/10.1242/jcs.091579.
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Del Rosso, Mario. "uPAR in angiogenesis regulation." Blood 117, no. 15 (April 14, 2011): 3941–43. http://dx.doi.org/10.1182/blood-2011-02-337733.
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Shetty, S., A. Kumar, and S. Idell. "Posttranscriptional regulation of urokinase receptor mRNA: identification of a novel urokinase receptor mRNA binding protein in human mesothelioma cells." Molecular and Cellular Biology 17, no. 3 (March 1997): 1075–83. http://dx.doi.org/10.1128/mcb.17.3.1075.
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Treatment of human pleural mesothelioma (MS-1) cells with phorbol myristate acetate (PMA) and cycloheximide results in 17- and 10-fold, respectively, increases in steady-state expression of urokinase-type plasminogen activator receptor (uPAR) mRNA. Studies of transcriptional inhibition by actinomycin D showed four- and sixfold extensions of uPAR mRNA half-life in MS-1 cells treated with PMA and cycloheximide, respectively, suggesting that uPAR gene expression involves a posttranscriptional regulatory mechanism. Using gel mobility shift and UV cross-linking assays, we identified a 50-kDa uPAR mRNA binding protein (uPAR mRNABp) that selectively bound to a 51-nucleotide (nt) fragment of mRNA corresponding to the uPAR coding region. We investigated the possibility that this 51-nt protein binding fragment of uPAR mRNA contains regulatory information for message stability. Chimeric beta-globin/uPAR/beta-globin mRNA containing the 51-nt protein binding fragment was able to destabilize otherwise stable beta-globin mRNA. Conversely, a control chimeric beta-globin/uPAR/beta-globin mRNA containing a 51-nt fragment of the uPAR coding region that does not bind uPAR mRNABp was stable under identical conditions. Binding of uPAR mRNABp to uPAR mRNA was abolished after treatment with cycloheximide and rapidly down-regulated by PMA. These data suggest that the 51-nt protein binding fragment of uPAR mRNA may be involved in mRNA turnover as well as in cycloheximide-induced uPAR message stabilization. Our results indicate a novel mechanism of uPAR gene regulation in which cis elements within a 51-nt coding region interact with a uPAR mRNABp to regulate uPAR message stability.
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Shetty, Sreerama, Thirunavukkarasu Velusamy, Steven Idell, Hua Tang, and Praveen Kumar Shetty. "Regulation of urokinase receptor expression by protein tyrosine phosphatases." American Journal of Physiology-Lung Cellular and Molecular Physiology 292, no. 2 (February 2007): L414—L421. http://dx.doi.org/10.1152/ajplung.00121.2006.
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Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play a major role in several physiological processes such as cell migration, proliferation, morphogenesis, and regulation of gene expression. Many of the biological activities of uPA depend on its association with uPAR. uPAR expression and its induction by uPA are regulated at the posttranscriptional level. Inhibition of protein tyrosine phosphatase-mediated dephosphorylation by sodium orthovanadate induces uPAR expression and, with uPA, additively induces cell surface uPAR expression. Sodium orthovanadate induces uPAR by increasing uPAR mRNA in a time- and concentration-dependent manner. Both sodium orthovanadate and uPA induce uPAR mRNA stability, indicating that dephosphorylation could contribute to uPA-induced posttranscriptional regulation of uPAR expression. Induction of the tyrosine phosphatase SHP2 in Beas2B and H157 cells inhibits basal cell surface uPAR expression and uPA-induced uPAR expression. Sodium orthovanadate also increases uPAR expression by decreasing the interaction of a uPAR mRNA coding region sequence with phosphoglycerate kinase (PGK) as well as by enhancing the interaction between a uPAR mRNA 3′ untranslated sequence with heterogeneous nuclear ribonucleoprotein C (hnRNPC). On the contrary, overexpression of SHP2 in Beas2B cells increased interaction of PGK with the uPAR mRNA coding region and inhibited hnRNPC binding to the 3′ untranslated sequence. These findings confirm a novel mechanism by which uPAR expression of lung airway epithelial cells is regulated at the level of mRNA stability by inhibition of protein tyrosine phosphatase-mediated dephosphorylation of uPAR mRNA binding proteins and demonstrate that the process involves SHP2.
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Matsuno, Hiroyuki, Eri Kawashita, Kiyotaka Okada, Hidetaka Suga, Shigeru Ueshima, Osamu Matsuo, and Yosuke Kanno. "Urokinase-type plasminogen activator receptor is associated with the development of adipose tissue." Thrombosis and Haemostasis 104, no. 12 (2010): 1124–32. http://dx.doi.org/10.1160/th10-02-0101.
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SummaryUrokinase-type plasminogen activator receptor (uPAR) plays a role in cellular responses which include cellular adhesion, differentiation, proliferation and migration. The aim of this study was to clarify the role of uPAR on the development of adipose tissue. To clarify the role of uPAR on adipogenesis, we examined the effect of uPAR overexpression and uPAR deficiency on the adipocyte differentiation. Adipocyte differentiation was induced by incubation of 3T3-L1 cells with differentiation media containing insulin, dexamethasone, and 1-methyl-3-isobutylxanthin. uPAR overexpression by transfection of uPAR expression vector induced adipocyte differentiation. In addition, we examined the difference in adipocyte differentiation of mesenchymal stem cells from wild-type mice and uPAR knockout (uPAR-/-) mice. The uPAR deficiency attenuated differentiation media-induced adipocyte differentiation. Moreover, we found that the inhibition of phosphatidylinositol 3-kinase (PI3K) pathway attenuated uPAR overexpression-induced adipocyte differentiation, and uPAR overexpression induced the activation of Akt. We also found that an increase of the adipose tissue mass in uPAR-/- mice was less than that observed in wild-type mice. The present results suggest that uPAR plays a pivotal role in the development of adipose tissue through PI3K/Akt pathway.
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Shetty, Sreerama, Thirunavukkarasu Velusamy, Steven Idell, Praveenkumar Shetty, Andrew P. Mazar, Yashodhar P. Bhandary, and Rashmi S. Shetty. "Regulation of Urokinase Receptor Expression by p53: Novel Role in Stabilization of uPAR mRNA." Molecular and Cellular Biology 27, no. 16 (June 4, 2007): 5607–18. http://dx.doi.org/10.1128/mcb.00080-07.
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ABSTRACT We found that p53-deficient (p53−/−) lung carcinoma (H1299) cells express robust levels of cell surface uPAR and uPAR mRNA. Expression of p53 protein in p53−/− cells suppressed basal and urokinase (uPA)-induced cell surface uPAR protein and increased uPAR mRNA degradation. Inhibition of p53 by RNA silencing in Beas2B human airway epithelial cells conversely increased basal as well as uPA-mediated uPAR expression and stabilized uPAR mRNA. Purified p53 protein specifically binds to the uPAR mRNA 3′ untranslated region (3′UTR), and endogenous uPAR mRNA associates with p53. The p53 binding region involves a 37-nucleotide uPAR 3′UTR sequence, and insertion of the p53 binding sequence into β-globin mRNA destabilized β-globin mRNA. Inhibition of p53 expression in these cells reverses decay of chimeric β-globin-uPAR mRNA. These observations demonstrate a novel regulatory role for p53 as a uPAR mRNA binding protein that down-regulates uPAR expression, destabilizes uPAR mRNA, and thereby contributes to the viability of human airway epithelial or lung carcinoma cells.
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Prager, Gerald, Rene Novotny, Matthias Unseld, Marina Poettler, Waclawa Kalinowska, Johannes Breuss, and Christoph Zielinski. "Urokinase-Type Plasminogen Activator Receptor (uPAR, CD87) Regulates Integrin Redistribution in Endothelial Cells Via Interaction with Low Density Lipoprotein Receptor- (LDLR-) Like Proteins." Blood 118, no. 21 (November 18, 2011): 5315. http://dx.doi.org/10.1182/blood.v118.21.5315.5315.
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Abstract Abstract 5315 angiogenesis by degradation of extracellular matrix proteins as well as induction of intracellular signal transduction. We recently could demonstrate that in VEGF-stimulated endothelial cells pro-uPA becomes activated, which leads to uPAR-complex formation, it's internalization and redistribution of uPAR to newly formed focal adhesions ad the leading edge of migrating endothelial cells. Thereby, uPAR surface expression is tightly transcriptional regulated via the Density Enhanced Phosphatase-1 (DEP-1), but also via the LDLR-family members, which regulate subcellular uPAR distribution. Here, we describe a mechanisms by which uPAR-internalization regulates integrin redistribution. We have characterized a novel binding motif on uPAR domain 3 for LDLR-protein interaction by using affinity chromatography as well as co-immunoprecipitation experiments. To proof a functional relevance of a direct uPAR/LDLR protein interaction, we reconstituted either uPAR mutants (mutL3/uPAR), lacking the binding site for LDLR-proteins, or wild type uPAR into endothelial cells derived from uPAR−/− mice. Reconstitution of mutL3/uPAR was incapable to redistribute uPAR as well as integrins during VEGF-induced endothelial cell migration when compared to wild type uPAR reconstitutes. The functional importance of uPAR / LDLR interaction was further reflected by the use of an inhibitory peptide (P1) interfering with uPAR/LDLR-protein interaction, which functionally reverted full length uPAR reconstitution, or the chaperon Receptor Associated Protein (RAP), a high affinity ligand for LDLR-proteins, which prevents uPAR/LDLR interactions. Thus, interfering with uPAR/LDLR-protein interaction at different levels led to an impaired endothelial cell spreading behavior on integrin-adhesive matrix proteins as well as a reduced pY576 FAK phosphorylation upon endothelial cell adhesion, leading to an reduced migratory response towards VEGF. These data suggest a central role of uPAR/LDLR-protein interaction in VEGF-induced endothelial cell migration via induction of integrin redistribution. Thus, uPAR/LDLR interaction might represent a novel therapeutic target in angiogenesis-related diseases. Disclosures: No relevant conflicts of interest to declare.
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Piironen, Timo, Birgitte Laursen, Jesper Pass, Karin List, Henrik Gårdsvoll, Michael Ploug, Keld Danø, and Gunilla Høyer-Hansen. "Specific Immunoassays for Detection of Intact and Cleaved Forms of the Urokinase Receptor." Clinical Chemistry 50, no. 11 (November 1, 2004): 2059–68. http://dx.doi.org/10.1373/clinchem.2004.038232.
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Abstract Background: The cell surface receptor (uPAR) for urokinase plasminogen activator (uPA) is a strong prognostic marker in several types of cancer. uPA cleaves the three-domain protein uPAR(I-III) into two fragments: uPAR(I), which contains domain I; and uPAR(II-III), which contains domains II and III. Established immunoassays measure a combination of uPAR forms. Our aim was to design immunoassays for specific quantification of the individual forms of uPAR. Methods: Using appropriate combinations of epitope-mapped monoclonal antibodies (Mabs) for capture and europium-labeled detection Mabs, we designed two-site sandwich time-resolved fluorescence immunoassays (TR-FIAs): TR-FIA 1 to measure uPAR(I-III) alone; TR-FIA 2 to measure both uPAR(I-III) and uPAR(II-III); and TR-FIA 3 to measure uPAR(I). To avoid detection of uPAR(I-III) in TR-FIA 3, we used a combination of the peptide uPAR antagonist AE120 and a domain I antibody, R3. AE120 blocks the binding of R3 to uPAR(I-III). In contrast, AE120 does not interact with liberated domain I and therefore does not interfere with the binding of R3 to uPAR(I). Results: The limits of quantification (CV <20%) determined by adding the proteins to uPAR-depleted plasma were <3 pmol/L in all three assays. The interassay CVs in plasma with added analytes were <11%, and recoveries were between 93% and 105%. Cross-reactivities of purified proteins in the three TR-FIAs were no more than 4%. Studies on chymotrypsin cleavage of uPAR and size-exclusion chromatography of plasma with and without added protein further supported the specificity of the assays. Conclusions: The three novel TR-FIAs accurately quantify uPAR(I-III) alone, uPAR(I-III) together with uPAR(II-III), and uPAR(I), respectively, in biological samples, including plasma, and thus are well suited for studies of the diagnostic and prognostic value of individual uPAR forms in cancer patients.
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Piironen, Timo, Alexander Haese, Hartwig Huland, Thomas Steuber, Ib Jarle Christensen, Nils Brünner, Keld Danø, Gunilla Høyer-Hansen, and Hans Lilja. "Enhanced Discrimination of Benign from Malignant Prostatic Disease by Selective Measurements of Cleaved Forms of Urokinase Receptor in Serum." Clinical Chemistry 52, no. 5 (May 1, 2006): 838–44. http://dx.doi.org/10.1373/clinchem.2005.064253.
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Abstract Background: Early detection of prostate cancer (PCa) centers on measurements of prostate-specific antigen (PSA), but current testing practices suffer from lack of specificity and generate many unnecessary prostate biopsies. Soluble urokinase plasminogen activator receptor (uPAR) is present in blood in both intact and cleaved forms. Increased uPAR in blood is correlated with poor prognosis in various cancers, but uPAR has not been shown to be useful in PCa diagnostics. We assessed the ability of immunoassays for specific uPAR forms to discriminate PCa from benign conditions. Methods: We measured total PSA (tPSA), free PSA (fPSA), intact uPAR [uPAR(I-III)], intact uPAR + cleaved uPAR domains II+III [uPAR(I-III) + uPAR(II-III)], and cleaved uPAR domain I [uPAR(I)] in sera from 224 men with and 166 men without PCa. We assessed differences in serum concentrations between the PCa and noncancer groups within the entire cohort and in men with tPSA concentrations of 2–10 μg/L. The diagnostic accuracy of individual analytes and analyte combinations was explored by logistic regression and ROC analyses and evaluations of sensitivity and specificity pairs. Results: Serum uPAR(I) and uPAR(II-III) were higher in PCa than in benign disease. In men with tPSA between 2 and 10 μg/L, the combination of %fPSA with the ratio uPAR(I)/uPAR(I-III) had a greater area under the ROC curve (0.73) than did %fPSA (0.68). Conclusions: Specific measurements of different uPAR forms in serum improve the specificity of PCa detection. The uPAR forms may therefore be complementary to PSA for PCa detection, most importantly in men with moderately increased PSA.
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Dekkers, Pascale E. P., Tessa ten Hove, Anje A. te Velde, Sander J. H. van Deventer, and Tom van der Poll. "Upregulation of Monocyte Urokinase Plasminogen Activator Receptor during Human Endotoxemia." Infection and Immunity 68, no. 4 (April 1, 2000): 2156–60. http://dx.doi.org/10.1128/iai.68.4.2156-2160.2000.
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ABSTRACT The receptor for urokinase-type plasminogen activator (uPAR) (CD87) plays an important role in leukocyte adhesion and migration. To assess the effect of endotoxin on cellular uPAR, uPAR expression was determined on leukocytes by fluorescence-activated cell sorter analysis in seven healthy subjects following intravenous injection of endotoxin (lot G; 4 ng/kg). Endotoxin induced a transient increase in uPAR expression on monocytes, reaching a 92% ± 46% increase over baseline expression after 6 h (P < 0.05). Endotoxin did not influence uPAR expression on granulocytes, while uPAR remained undetectable on lymphocytes. Endotoxin also increased soluble uPAR levels in plasma (P < 0.05). Stimulation of human whole blood with endotoxin or gram-positive stimuli in vitro also resulted in an upregulation of monocyte uPAR expression. Although tumor necrosis factor alpha (TNF) upregulated monocyte uPAR expression, anti-TNF did not influence the endotoxin-induced increase in monocyte uPAR expression. These data suggest that infectious stimuli may influence monocyte function in vivo by enhancing the expression of uPAR.
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Shetty, Sreerama, and Steven Idell. "A urokinase receptor mRNA binding protein from rabbit lung fibroblasts and mesothelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 274, no. 6 (June 1, 1998): L871—L882. http://dx.doi.org/10.1152/ajplung.1998.274.6.l871.
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The urokinase receptor (uPAR) influences several biological functions relevant to lung injury and repair, including proteolysis, cell migration, and adhesion. In malignant mesothelioma cells, we recently found that a posttranscriptional mechanism involving a cis- transinteraction between a uPAR mRNA sequence and a cytoplasmic uPAR mRNA binding protein (mRNABP) regulates uPAR gene expression (S. Shetty, A. Kumar, and S. Idell. Mol. Cell Biol. 17: 1075–1083, 1997). In this study, we sought to determine if uPAR expression in lung and pleural cells involves a similar posttranscriptional pathway. We first identified and characterized the uPAR mRNABP in rabbit tissues using gel mobility shift, ultraviolet (UV) cross-linking, and RNase protection assays and detected it in liver, heart, brain, spleen, colon, and lung. Phorbol 12-myristate 13-acetate, lipopolysaccharide, transforming growth factor-β, tumor necrosis factor-α, or cycloheximide induced uPAR and uPAR mRNA expression in cultured rabbit pleural mesothelial cells and lung fibroblasts and concurrently reduced the uPAR mRNA-uPAR mRNABP interaction. Using conventional and affinity chromatography, we purified a 50-kDa uPAR mRNABP that selectively binds to a 51-nucleotide fragment of the uPAR coding region. This protein migrates as a monomer when analyzed by SDS-PAGE and UV cross-linking and does not possess intrinsic RNase activity in vitro. A uPAR mRNABP physicochemically and functionally similar to that of human malignant mesothelioma is constitutively expressed in the rabbit lung and other nonneoplastic tissues. In rabbit lung fibroblasts and mesothelial cells, expression of uPAR involves posttranscriptional regulation whereby the uPAR mRNABP appears to interact with a specific coding region cis-element to decrease the stability of uPAR mRNA.
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Mekkawy, Ahmed H., David L. Morris, and Mohammad H. Pourgholami. "HAX1 Augments Cell Proliferation, Migration, Adhesion, and Invasion Induced by Urokinase-Type Plasminogen Activator Receptor." Journal of Oncology 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/950749.
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The urokinase-type plasminogen activator receptor (uPAR) is a cell surface receptor which has a multifunctional task in the process of tumorigenesis including cell proliferation, adhesion, migration, and invasion. Many of the biological functions of uPAR necessitate interactions with other proteins. We have shown previously that uPAR interacts with HAX1 protein (HS-1-associated protein X-1). In the current study, to gain insight into the possible role of HAX1 overexpression in regulation of uPAR signal transduction pathway, several function assays were used. We found that, upon stimulation of uPAR, HAX1 colocalizes with uPAR suggesting a physiological role for HAX1 in the regulation of uPAR signal transduction. HAX1 overexpression augments cell proliferation and migration in uPAR-stimulated cells. Moreover, HAX1 over-expression augmented uPAR-induced cell adhesion to vitronectin as well as cellular invasion. Our results suggest that HAX1 over-expression may underlay a novel mechanism to regulate uPAR-induced functions in cancer cells.
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Mekkawy, Ahmed H., and David L. Morris. "Human Sprouty1 Suppresses Urokinase Receptor-Stimulated Cell Migration and Invasion." ISRN Biochemistry 2013 (September 12, 2013): 1–7. http://dx.doi.org/10.1155/2013/598251.
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The urokinase-type plasminogen activator receptor (uPAR) has been implicated in several processes in tumor progression including cell migration and invasion in addition to initiation of signal transduction. Since uPAR lacks a transmembrane domain, it uses the interaction with other proteins to modulate intracellular signal transduction. We have previously identified hSpry1 as a partner protein of uPAR, suggesting a physiological role for hSpry1 in the regulation of uPAR signal transduction. In this study, hSpry1 was found to colocalize with uPAR upon stimulation with epidermal growth factor (EGF), urokinase (uPA), or its amino terminal fragment (uPA-ATF), implicating a physiological role of hSpry1 in regulation of uPAR signalling pathway. Moreover, hSpry1 was able to inhibit uPAR-stimulated cell migration in HEK293/uPAR, breast carcinoma, and colorectal carcinoma cells. In addition, hSpry1 was found to inhibit uPAR-stimulated cell invasion in breast carcinoma and osteosarcoma cell lines. Increasing our understanding of how hSpry1 negatively regulates uPAR-stimulated cellular functions may determine a distinctive role for hSpry1 in tumour suppression.
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Czekay, Ralf-Peter, Thomas A. Kuemmel, Robert A. Orlando, and Marilyn Gist Farquhar. "Direct Binding of Occupied Urokinase Receptor (uPAR) to LDL Receptor-related Protein Is Required for Endocytosis of uPAR and Regulation of Cell Surface Urokinase Activity." Molecular Biology of the Cell 12, no. 5 (May 2001): 1467–79. http://dx.doi.org/10.1091/mbc.12.5.1467.
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Low-density lipoprotein receptor-related protein (LRP) mediates internalization of urokinase:plasminogen activator inhibitor complexes (uPA:PAI-1) and the urokinase receptor (uPAR). Here we investigated whether direct interaction between uPAR, a glycosyl-phosphatidylinositol–anchored protein, and LRP, a transmembrane receptor, is required for clearance of uPA:PAI-1, regeneration of unoccupied uPAR, activation of plasminogen, and the ability of HT1080 cells to invade extracellular matrix. We found that in the absence of uPA:PAI-1, uPAR is randomly distributed along the plasma membrane, whereas uPA:PAI-1 promotes formation of uPAR-LRP complexes and initiates redistribution of occupied uPAR to clathrin-coated pits. uPAR-LRP complexes are endocytosed via clathrin-coated vesicles and traffic together to early endosomes (EE) because they can be coimmunoprecipitated from immunoisolated EE, and internalization is blocked by depletion of intracellular K+. Direct binding of domain 3 (D3) of uPAR to LRP is required for clearance of uPA-PAI-1–occupied uPAR because internalization is blocked by incubation with recombinant D3. Moreover, uPA-dependent plasmin generation and the ability of HT1080 cells to migrate through Matrigel-coated invasion chambers are also inhibited in the presence of D3. These results demonstrate that GPI-anchored uPAR is endocytosed by piggybacking on LRP and that direct binding of occupied uPAR to LRP is essential for internalization of occupied uPAR, regeneration of unoccupied uPAR, plasmin generation, and invasion and migration through extracellular matrix.
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Tjwa, Marc, Lieve Moons, Koen Theunissen, Rute Moura, Francesco Blasi, Mieke Dewerchin, Nicolai Sidenius, Desire Collen, and Peter Carmeliet. "Role of Plasmin and uPAR in Bone Marrow HSC/HPC Retention and Mobilization." Blood 106, no. 11 (November 16, 2005): 472. http://dx.doi.org/10.1182/blood.v106.11.472.472.
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Abstract We previously identified the plasmin protease family as a critical determinant of the mobilization of hematopoietic stem and progenitor cells (HSC/HPC), but the role of the urokinase receptor uPAR remained unclear. uPAR is a membrane-anchored glycoprotein, which not only localizes its ligand urokinase (uPA) to the cell surface via its GPI-anchor but also regulates β1-integrin dependent cell adhesion and migration. Following 5-FU myeloablation or G-CSF treatment, mice lacking uPAR (uPAR−/−) had impaired hematopoietic recovery and HSC/HPC mobilization as compared to wild type (WT) mice. However, this phenotype was not mimicked in mice lacking uPA, suggesting a role of uPAR in mobilization independent of uPA-mediated proteolysis. The impaired mobilization in uPAR−/− mice was reversed upon pre-transplantation with WT BM cells (BMC), suggesting functional expression of uPAR on transplantable BMCs. Conversely, loss or inhibition of uPAR on transplanted BMCs impaired homing to the BM but not to the spleen, and compromised survival of myeloablated WT recipients. In vitro experiments revealed that loss or inhibition of uPAR impaired BMC adhesion to stromal cells and fibronectin. Anti-α4-β1 antibodies blocked adhesion of WT but not uPAR−/− BMCs. Thus, uPAR appears to regulate BM homing and α4-β1 dependent retention of transplantable BMCs, possibly HSC/HPCs. If uPAR mediates retention of HSC/HPCs, then this signal should be inactivated upon mobilization. Indeed, in 5-FU or G-CSF-treated WT mice, we found increased uPAR cleavage, and elevated levels of soluble uPAR (suPAR) in BM plasma. These processes failed to occur in mice lacking plasminogen, suggesting that plasmin cleaves uPAR during mobilization. Cleavage of uPAR appeared critical as the inactivation of the retention signals membrane-bound Kit ligand and SDF-1α was normal in uPAR−/− mice. Moreover, the generated suPAR may also affect the BM, as administration of recombinant suPAR in WT mice enhanced hematopoietic recovery and HSC/HPC mobilization after 5-FU or G-CSF. In vitro and transplantation experiments revealed that suPAR blocked α4-β1 dependent adhesion. Thus, in steady state, membrane-anchored uPAR appears to function as a BM retention signal for transplantable BMCs, possibly HSC/HPCs. In conditions of mobilization, the uPAR retention signal is cleaved, which weakens α4-β1 dependent adhesion and allows mobilization out of the BM. Soluble uPAR may then additionally amplify mobilization, in part by further attenuating α4-β1 dependent adhesion to the BM. Currently, we are investigating the role of uPAR on subsets of HSC/HPCs, and in the different BM niches. We are also performing long-term competitive repopulation experiments to further delineate the therapeutic potential of uPAR.
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Ghiso, Julio A. Aguirre, Katherine Kovalski, and Liliana Ossowski. "Tumor Dormancy Induced by Downregulation of Urokinase Receptor in Human Carcinoma Involves Integrin and MAPK Signaling." Journal of Cell Biology 147, no. 1 (October 4, 1999): 89–104. http://dx.doi.org/10.1083/jcb.147.1.89.
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Mechanisms that regulate the transition of metastases from clinically undetectable and dormant to progressively growing are the least understood aspects of cancer biology. Here, we show that a large (∼70%) reduction in the urokinase plasminogen activator receptor (uPAR) level in human carcinoma HEp3 cells, while not affecting their in vitro growth, induced a protracted state of tumor dormancy in vivo, with G0/G1 arrest. We have now identified the mechanism responsible for the induction of dormancy. We found that uPA/uPAR proteins were physically associated with α5β1, and that in cells with low uPAR the frequency of this association was significantly reduced, leading to a reduced avidity of α5β1 and a lower adhesion of cells to the fibronectin (FN). Adhesion to FN resulted in a robust and persistent ERK1/2 activation and serum-independent growth stimulation of only uPAR-rich cells. Compared with uPAR-rich tumorigenic cells, the basal level of active extracellular regulated kinase (ERK) was four to sixfold reduced in uPAR-poor dormant cells and its stimulation by single chain uPA (scuPA) was weak and showed slow kinetics. The high basal level of active ERK in uPAR-rich cells could be strongly and rapidly stimulated by scuPA. Disruption of uPAR–α5β1 complexes in uPAR-rich cells with antibodies or a peptide that disrupts uPAR–β1 interactions, reduced the FN-dependent ERK1/2 activation. These results indicate that dormancy of low uPAR cells may be the consequence of insufficient uPA/uPAR/α5β1 complexes, which cannot induce ERK1/2 activity above a threshold needed to sustain tumor growth in vivo. In support of this conclusion we found that treatment of uPAR-rich cells, which maintain high ERK activity in vivo, with reagents interfering with the uPAR/β1 signal to ERK activation, mimic the in vivo dormancy induced by downregulation of uPAR.
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Yuan, Cai, Zhanzhi Guo, Shujuan Yu, Longguang Jiang, and Mingdong Huang. "Development of inhibitors for uPAR: blocking the interaction of uPAR with its partners." Drug Discovery Today 26, no. 4 (April 2021): 1076–85. http://dx.doi.org/10.1016/j.drudis.2021.01.016.
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Shetty, Sreerama, Malathesha Ganachari, Ming-Cheh Liu, Ali Azghani, Harish Muniyappa, and Steven Idell. "Regulation of urokinase receptor expression by phosphoglycerate kinase is independent of its catalytic activity." American Journal of Physiology-Lung Cellular and Molecular Physiology 289, no. 4 (October 2005): L591—L598. http://dx.doi.org/10.1152/ajplung.00319.2004.
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Posttranscriptional regulation of urokinase-type plasminogen activator receptor (uPAR) mRNA involves the interaction of a uPAR mRNA coding region sequence with phosphoglycerate kinase (PGK), a 50-kDa uPAR mRNA binding protein. PGK catalyzes a reversible transfer of a phosphoryl group from 1,3-biphosphoglycerate to ADP in the glycolytic pathway. Our previous studies showed that overexpression of PGK in uPAR-overproducing H157 lung carcinoma cells results in decreased cytoplasmic uPAR mRNA and cell surface uPAR protein expression through destabilization of the mRNA. In order to determine the role of PGK enzymatic activity on uPAR mRNA stability we mutated PGK by changing amino acid P204H and amino acid D219A. The mutant proteins were expressed in Epicurian coli BL21 cells, and the purified proteins were analyzed for PGK activity. We found that mutation of amino acid P204H and D219A reduced PGK activity by 99 and 83%, respectively. By gel mobility shift and Northwestern assay, we found that the mutant proteins were able to bind to uPAR mRNA as effectively as wild-type PGK. Overexpression of mutant, inactive PGK in H157 cells reduced cell surface uPAR protein as well as uPAR mRNA expression. Run-on transcription analysis indicated that overexpression of mutant PGKs fails to alter the rate of synthesis of uPAR mRNA, whereas transcription chase experiments demonstrated that both mutants and wild-type PGK reduce the stability of the uPAR mRNA transcripts to a similar extent. Overexpression of mutant PGK also inhibited the rate of DNA synthesis and the invasion-migration ratio. These results demonstrate that uPAR mRNA binding activity as well as PGK-mediated regulation of uPAR mRNA are independent of PGK enzymatic activity.
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Bernstein, Audrey M., Sally S. Twining, Debra J. Warejcka, Edward Tall, and Sandra K. Masur. "Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation." Molecular Biology of the Cell 18, no. 7 (July 2007): 2716–27. http://dx.doi.org/10.1091/mbc.e06-10-0912.
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Fibroblasts migrate into and repopulate connective tissue wounds. At the wound edge, fibroblasts differentiate into myofibroblasts, and they promote wound closure. Regulated fibroblast-to-myofibroblast differentiation is critical for regenerative healing. Previous studies have focused on the role in fibroblasts of urokinase plasmingen activator/urokinase plasmingen activator receptor (uPA/uPAR), an extracellular protease system that promotes matrix remodeling, growth factor activation, and cell migration. Whereas fibroblasts have substantial uPA activity and uPAR expression, we discovered that cultured myofibroblasts eventually lost cell surface uPA/uPAR. This led us to investigate the relevance of uPA/uPAR activity to myofibroblast differentiation. We found that fibroblasts expressed increased amounts of full-length cell surface uPAR (D1D2D3) compared with myofibroblasts, which had reduced expression of D1D2D3 but increased expression of the truncated form of uPAR (D2D3) on their cell surface. Retaining full-length uPAR was found to be essential for regulating myofibroblast differentiation, because 1) protease inhibitors that prevented uPAR cleavage also prevented myofibroblast differentiation, and 2) overexpression of cDNA for a noncleavable form of uPAR inhibited myofibroblast differentiation. These data support a novel hypothesis that maintaining full-length uPAR on the cell surface regulates the fibroblast to myofibroblast transition and that down-regulation of uPAR is necessary for myofibroblast differentiation.
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Bass, Rosemary, and Vincent Ellis. "Regulation of urokinase receptor function and pericellular proteolysis by the integrin α5β1." Thrombosis and Haemostasis 101, no. 05 (2009): 954–62. http://dx.doi.org/10.1160/th08-08-0558.
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SummaryInteractions between the uPA receptor (uPAR) and various inte-grins, including α5β1, are known to modulate integrin-dependent cell adhesion, and we have shown that the integrin-associated tetraspanin protein CD82 down-regulates uPAR-dependent plasminogen activation by affecting α5β1 cellular localisation. Here we have investigated whether overexpression of α5β1 directly affects uPAR-dependent pericellular proteolysis. CHO cells overexpressing α5β1 were found to activate plasminogen at a rate up to 18-fold faster than B2CHO cells which are α5-deficient. This effect was dependent on the activation state of α5β1, as it was maximal in the presence of Mn2+. To determine the role of uPAR-α5β1 interactions in this effect, we determined the adhesion of these cells to immobilised soluble uPAR (suPAR). Neither cell-type was found to adhere to suPAR, but both cell types were found to adhere to an anti-uPAR monoclonal antibody in a uPAR- and integrin-dependent manner. This adhesion was 10-fold greater in the absence of α5β1, possibly implicating the involvement of non-α5-integrins. Soluble forms of the various components were used to investigate the molecular basis of these effects, but no direct interactions could be demonstrated between α5β1 and either uPAR, uPA or uPA-uPAR complex. This suggests that assembly of these components on the plasma membrane is required to influence uPAR function, increasing uPAR-dependent pericellular proteolysis and decreasing uPAR-dependent cell adhesion. These interactions may be modified by other integrins, suggesting a complex interplay between uPAR and integrins on the cell surface with the potential to regulate invasive cell migration.
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Smaradhania, Nilam, Septiman Rahman, Salman Ardi Syamsu, and Prihantono Prihantono. "Urokinase type plasminogen activator receptor (uPAR) and human epidermal growth factor receptor 2 (HER2) expression in metastasis of breast cancer." Breast Disease 40 (June 25, 2021): S1—S7. http://dx.doi.org/10.3233/bd-219001.
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BACKGROUND: The plasminogen urokinase activation system consists of urokinase plasminogen activator (uPA), its receptor uPAR, and plasminogen activator inhibitor type 1 (PAI-1), which are considered to have a relationship with cancer aggressiveness. Several studies have found correlations between HER2 mRNA and uPAR in disseminated tumor cells (DTCs) in breast cancer patients. They are associated with a more aggressive primary tumor phenotype and recurrence/metastasis. OBJECTIVE: This study aims to determine the relationship between the expression of urokinase-type plasminogen activator receptor (uPAR) and human epidermal growth factor receptor type 2 (HER2) with the incidence of distant metastases in breast cancer. METHODS: This study was an observational study using a cross-sectional method and was conducted at Wahidin Sudirohusodo Hospital and the network. Immunohistochemical methods carry out examination of uPAR and HER2 expression from tissues of breast cancer patients. The relationship of uPAR, HER2 expression, and metastasis was tested with the Mann Whitney test. RESULTS: The study results found that the proportion of patients with metastasis was significantly higher in high uPAR expression compared to low uPAR (77.8% compared to 36.8%). The negative HER2 expression was significantly higher in the low uPAR expression than the high uPAR (78.9% compared to 33.3%). In comparison, the positive HER2 expression was significantly higher in the high uPAR expression than the low uPAR (66.7% compared to 21.1%). In positive HER2 expression, the mean percentage of uPAR expression was significantly higher in metastases than those without metastasis (72.7% compared to 42.1%). CONCLUSIONS: uPAR expression is associated with metastasis in HER2 positive breast cancer.
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Thurison, Tine, Anne F. Lomholt, Morten G. Rasch, Ida K. Lund, Hans J. Nielsen, Ib J. Christensen, and Gunilla Høyer-Hansen. "A New Assay for Measurement of the Liberated Domain I of the Urokinase Receptor in Plasma Improves the Prediction of Survival in Colorectal Cancer." Clinical Chemistry 56, no. 10 (October 1, 2010): 1636–40. http://dx.doi.org/10.1373/clinchem.2010.144410.
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BACKGROUND The liberated domain I of the urokinase plasminogen activator receptor [uPAR(I)] is a significant prognostic marker in lung and ovarian cancer, although the uPAR(I) concentration is below the limit of quantification (LOQ) in a substantial proportion of patient samples (Lung Cancer 2005;48:349–55; Clin Cancer Res 2008;14:5785–93; APMIS 2009;117:755–61). This study was undertaken to design an immunoassay with improved functional sensitivity for measuring uPAR(I) and to evaluate the prognostic value of uPAR(I) for colorectal cancer (CRC) patients. METHODS Surface plasmon resonance analysis identified 2 monoclonal antibodies, R3 and R20, that simultaneously bind to the liberated uPAR(I) but not to intact uPAR. We used R3 for capture and Eu-labeled R20 for detection in designing a 2-site sandwich time-resolved fluorescence immunoassay (TR-FIA 4) for measuring liberated uPAR(I). TR-FIA 4 was validated for use with citrated plasma. The prognostic value of the uPAR(I) concentration was evaluated in 298 CRC patients. The Cox proportional hazards model was used for the uni- and multivariate survival analyses. RESULTS The LOQ was 0.65 pmol/L. Liberated uPAR(I) was measurable in all patient samples with TR-FIA 4. In the multivariate analysis that included sex, age, tumor stage, tumor localization, and adjuvant treatment, the uPAR(I) concentration measured with TR-FIA 4 (hazard ratio, 1.72; 95% CI, 1.15–2.57; P = 0.009), as well as the concentration of intact soluble uPAR plus the cleaved uPAR fragment containing domains II and III, tumor stage, and age were independent predictors of prognosis. CONCLUSIONS TR-FIA 4 has a functional sensitivity improved 4-fold over that of the previous uPAR(I) assay. The uPAR(I) concentration measured with TR-FIA 4 is an independent predictor of prognosis in CRC patients.
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Rinaldi, Loredana, Vincenza Elena Anna Rea, Nunzia Montuori, Vincenzo Cosimato, Daniela Alfano, and Pia Ragno. "uPAR regulates pericellular proteolysis through a mechanism involving integrins and fMLF-receptors." Thrombosis and Haemostasis 109, no. 02 (2013): 309–18. http://dx.doi.org/10.1160/th12-08-0546.
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SummaryThe expression of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR) can be regulated by several hormones, cytokines, and tumour promoters. uPAR is a glycosyl-phosphatidyl inositol (GPI)- linked cell-surface protein; however, it is capable to transduce signals inside the cell by interacting with other cell-surface proteins, such as integrins and G-protein coupled (GPC) receptors. We previously reported that uPAR cell-surface expression can be positively regulated by its ligand, uPA, independently of its proteolytic activity. We now demonstrate that uPAR overexpression induces or increases uPA secretion both in uPAR-negative and in uPAR-expressing cells. Accordingly, uPAR depletion impairs uPA expression in cells which constitutively express both uPA and its receptor. uPAR exerts its regulatory effect through the activation of the ERK mitogen-activated protein kinases (MAPKs), whereas the p-38 MAPK is not involved. Overexpression of truncated forms of uPAR, lacking the N-terminal domain (DI) and not able to interact with membrane co-receptors, failed to increase uPA expression. Inhibition of uPAR-integrin interaction by the specific P-25 peptide, as well as Gi-protein inhibition by cholera pertussin toxin or depletion of the GPC receptors for fMLF (fMLF-Rs) also impaired uPAR capability to regulate uPA expression. These findings demonstrate that uPAR, whose expression is regulated by uPA, can, in turn, regulate uPA expression through a mechanism involving its functional interaction with integrins and fMLF-Rs.
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Unseld, Matthias, Anastasia Chilla, Clemens Pausz, Rula Mawas, Johannes Breuss, Christoph Zielinski, Gernot Schabbauer, and Gerald Prager. "PTEN expression in endothelial cells is down-regulated by uPAR to promote angiogenesis." Thrombosis and Haemostasis 114, no. 08 (2015): 379–89. http://dx.doi.org/10.1160/th15-01-0016.
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SummaryThe tumour suppressor phosphatase and tensin homologue (PTEN), mutated or lost in many human cancers, is a major regulator of angiogenesis. However, the cellular mechanism of PTEN regulation in endothelial cells so far remains elusive. Here, we characterise the urokinase receptor (uPAR, CD87) and its tumour-derived soluble form, suPAR, as a key molecule of regulating PTEN in endothelial cells. We observed uPAR-deficient endothelial cells to express enhanced PTEN mRNA- and protein levels. Consistently, uPAR expression in endogenous negative uPAR cells, down-regulated PTEN and activated the PI3K/Akt pathway. Additionally, we found that integrin adhesion receptors act as trans-membrane signaling partners for uPAR to repress PTEN transcription in a NF-κB-dependent manner. Functional in vitro assays with endothelial cells, derived from uPAR-deficient and PTEN heterozygous crossbred mice, demonstrated the impact of uPAR- dependent PTEN regulation on cell motility and survival. In an in vivo murine angiogenesis model uPAR-deficient PTEN heterozygous animals increased the impaired angiogenic phenotype of uPAR knockout mice and were able to reverse the high invasive potential of PTEN heterozygots. Our data provide first evidence that endogenous as well as exogenous soluble uPAR down-regulated PTEN in endothelial cells to support angiogenesis. The uPAR-induced PTEN regulation might represent a novel target for drug interference, and may lead to the development of new therapeutic strategies in anti-angiogenic treatment.
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Pulukuri, Sai MuraliKrishna, Christopher S. Gondi, Sajani S. Lakka, Aman Jutla, Norman Estes, Meena Gujrati, and Jasti S. Rao. "RNA Interference-directed Knockdown of Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Inhibits Prostate Cancer Cell Invasion, Survival, and Tumorigenicity in Vivo." Journal of Biological Chemistry 280, no. 43 (August 26, 2005): 36529–40. http://dx.doi.org/10.1074/jbc.m503111200.
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The invasive ability of tumor cells plays a key role in prostate cancer metastasis and is a major cause of treatment failure. Urokinase plasminogen activator-(uPA) and its receptor (uPAR)-mediated signaling have been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. This study was undertaken to investigate the biological roles of uPA and uPAR in prostate cancer cell invasion and survival, and the potential of uPA and uPAR as targets for prostate cancer therapy. uPA and uPAR expression correlates with the metastatic potential of prostate cancer cells. Thus, therapies designed to inhibit uPA and uPAR expression would be beneficial. LNCaP, DU145, and PC3 are prostate cancer cell lines with low, moderate, and high metastatic potential, respectively, as demonstrated by their capacity to invade the extracellular matrix. In this study we utilized small hairpin RNAs (shRNAs), also referred to as small interfering RNAs, to target human uPA and uPAR. These small interfering RNA constructs significantly inhibited uPA and uPAR expression at both the mRNA and protein levels in the highly metastatic prostate cancer cell line PC3. Our data demonstrated that uPA-uPAR knockdown in PC3 cells resulted in a dramatic reduction of tumor cell invasion as indicated by a Matrigel invasion assay. Furthermore, simultaneous silencing of the genes for uPA and uPAR using a single plasmid construct expressing shRNAs for both uPA and uPAR significantly reduced cell viability and ultimately resulted in the induction of apoptotic cell death. RNA interference for uPA and uPAR also abrogated uPA-uPAR signaling to downstream target molecules such as ERK1/2 and Stat 3. In addition, our results demonstrated that intratumoral injection with the plasmid construct expressing shRNAs for uPA and uPAR almost completely inhibited established tumor growth and survival in an orthotopic mouse prostate cancer model. These findings uncovered evidence of a complex signaling network operating downstream of uPA-uPAR that actively advances tumor cell invasion, proliferation, and survival of prostate cancer cells. Thus, RNA interference-directed targeting of uPA and uPAR is a convenient and novel tool for studying the biological role of the uPA-uPAR system and raises the potential of its application for prostate cancer therapy.
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Jardi, Mercè, Julia Inglés-Esteve, Maria Burgal, Carmen Azqueta, Francisco Velasco, Chary López-Pedrera, Lindsey Miles, and Jordi Félez. "Distinct Patterns of Urokinase Receptor (uPAR) Expression by Leukemic Cells and Peripheral Blood Cells." Thrombosis and Haemostasis 76, no. 06 (1996): 1009–19. http://dx.doi.org/10.1055/s-0038-1650701.
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SummaryThe urinary type plasminogen activator, urokinase (uPA) is localized on the cell surface through the binding of a specific receptor, the uPA receptor (uPAR). The uPA localization enhances plasmin formation on the cell surface and facilitates cell migration. The cellular and tissue distribution of uPAR is not fully established. We have analyzed uPAR expression in nine leukemic cell lines of distinct lineages and maturational states and correlated this with expression of plasminogen receptors, tissue-type plasminogen activator (tPA) receptors and LDL receptor-related protein (LRP). The most immature and least differentiated cell line (an erythro-myeloid cell line) and cells of lymphoid lineage, did not express uPAR, whereas cells differentiated along the myelo-monocytic pathway displayed this receptor. Plasminogen and tPA receptors were expressed by all leukemic cell lines and by all nucleated peripheral blood cells but B and T lymphocytes were negative for cell surface expression of both uPAR and LRP while monocytes and neutrophils were positive for expression of both uPAR and LRP. PMA stimulation induced surface expression of uPAR in lymphocytes but did not induce expression of LRP by these cells. In contrast, lymphoid cell lines were negative for uPAR expression even after PMA stimulation, indicating differences in regulation of uPAR expression between lymphocytes and lymphoid cell lines. The pattern of uPAR expression on leukemic cell lines was also studied on bone marrow blast cells from leukemic patients. Only the most mature myeloid cells expressed uPAR on their surfaces. In contrast, M3 leukemic cells and other blast cells displaying lymphoid markers such as TdT (+) and/or CD2 (+) did not express intracellular or cell-surface associated uPAR, indicating an heterogeneity among these promyelo-cytic cells and suggesting that uPAR may be a useful marker for leukemia typing. Myeloid blast cells from some patients contained intracellular pools of uPAR but displayed no receptor on the cell surface, suggesting that translocation may be a mechanism regulating uPAR expression in these cells. The comparison of uPAR expression between these cell lines and peripheral blood cells and it correlation with plasminogen receptors, tPA receptors and LRP expression offers new insights regarding potential mechanisms for regulation of uPA-uP-AR-mediated pericellular proteolysis.
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Connolly, Brian M., Eun Young Choi, Henrik Gårdsvoll, Alexandra L. Bey, Brooke M. Currie, Triantafyllos Chavakis, Shihui Liu, et al. "Selective abrogation of the uPA-uPAR interaction in vivo reveals a novel role in suppression of fibrin-associated inflammation." Blood 116, no. 9 (September 2, 2010): 1593–603. http://dx.doi.org/10.1182/blood-2010-03-276642.
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The urokinase plasminogen activator receptor (uPAR) has emerged as a potential regulator of cell adhesion, cell migration, proliferation, differentiation, and cell survival in multiple physiologic and pathologic contexts. The urokinase plasminogen activator (uPA) was the first identified ligand for uPAR, but elucidation of the specific functions of the uPA-uPAR interaction in vivo has been difficult because uPA has important physiologic functions that are independent of binding to uPAR and because uPAR engages multiple ligands. Here, we developed a new mouse strain (PlauGFDhu/GFDhu) in which the interaction between endogenous uPA and uPAR is selectively abrogated, whereas other functions of both the protease and its receptor are retained. Specifically, we introduced 4 amino acid substitutions into the growth factor domain (GFD) of uPA that abrogate uPAR binding while preserving the overall structure of the domain. Analysis of PlauGFDhu/GFDhu mice revealed an unanticipated role of the uPA-uPAR interaction in suppressing inflammation secondary to fibrin deposition. In contrast, leukocyte recruitment and tissue regeneration were unaffected by the loss of uPA binding to uPAR. This study identifies a principal in vivo role of the uPA-uPAR interaction in cell-associated fibrinolysis critical for suppression of fibrin accumulation and fibrin-associated inflammation and provides a valuable model for further exploration of this multifunctional receptor.
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Wei, Ying, Johannes A. Eble, Zemin Wang, Jordan A. Kreidberg, and Harold A. Chapman. "Urokinase Receptors Promote β1 Integrin Function through Interactions with Integrin α3β1." Molecular Biology of the Cell 12, no. 10 (October 2001): 2975–86. http://dx.doi.org/10.1091/mbc.12.10.2975.
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The urokinase receptor (uPAR) is linked to cellular migration through its capacity to promote pericellular proteolysis, regulate integrin function, and mediate cell signaling in response to urokinase (uPA) binding. The mechanisms for these activities remain incompletely defined, although uPAR was recently identified as acis-acting ligand for the β2 integrin CD11b/CD18 (Mac-1). Here we show that a major β1 integrin partner for uPAR/uPA signaling is α3. In uPAR-transfected 293 cells uPAR complexed (>90%) with α3β1 and antibodies to α3 blocked uPAR-dependent vitronectin (Vn) adhesion. Soluble uPAR bound to recombinant α3β1 in a uPA-dependent manner (Kd< 20 nM) and binding was blocked by a 17-mer α3β1 integrin peptide (α325) homologous to the CD11b uPAR-binding site. uPAR colocalized with α3β1 in MDA-MB-231 cells and uPA (1 nM) enhanced spreading and focal adhesion kinase phosphorylation on fibronectin (Fn) or collagen type I (Col) in a pertussis toxin- and α325-sensitive manner. A critical role of α3β1 in uPA signaling was verified by studies of epithelial cells from α3-deficient mice. Thus, uPAR preferentially complexes with α3β1, promoting direct (Vn) and indirect (Fn, Col) pathways of cell adhesion, the latter a heterotrimeric G protein-dependent mechanism of signaling between α3β1 and other β1 integrins.
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Andolfo, Annapaola, William English, Massimo Resnati, Gillian Murphy, Francesco Blasi, and Nicolai Sidenius. "Metalloproteases Cleave the Urokinase-Type Plasminogen Activator Receptor in the D1-D2 Linker Region and Expose Epitopes not Present in the intact Soluble Receptor." Thrombosis and Haemostasis 88, no. 08 (2002): 298–306. http://dx.doi.org/10.1055/s-0037-1613202.
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SummaryProteolytic cleavage of the urokinase plasminogen activator receptor (uPA(R)) prevents the binding of uPA and vitronectin while generating biologically active uPAR fragments. We have recently shown that matrix metalloproteinase-12 (MMP-12) releases cellular uPAR-antigen from stimulated human micro-vascular endothelial cells providing a novel feedback mechanism between the plasminogen activation and MMP systems. We now show that MMP-12 and other MMPs directly and efficiently cleave uPAR at the Thr86||Tyr87 peptide bond located in the linker region connecting uPAR domains 1 and 2, releasing the major ligand binding domain 1 from the rest of the receptor. The possible biological importance of uPAR cleavage by MMPs is supported by the observation that also murine uPAR is cleaved by MMP-12 (at the Pro89||Gln90 peptide bond), despite the limited sequence homology between the linker regions. Using an antibody raised against the human uPAR linker region we show that this region of uPAR, which contains the chemotactic SRSRY epitope, is exposed upon MMP cleavage.
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Stroomberg, Hein Vincent, Gitte Kristensen, Kasper Drimer Berg, Solvej Lippert, Klaus Brasso, and Martin Andreas Røder. "The Association between Plasma Levels of Intact and Cleaved uPAR Levels and the Risk of Biochemical Recurrence after Radical Prostatectomy for Prostate Cancer." Diagnostics 10, no. 11 (October 28, 2020): 877. http://dx.doi.org/10.3390/diagnostics10110877.
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Radical prostatectomy (RP) is a curatively intended treatment option for clinically localized non-metastatic prostate cancer (PCa). Novel biomarkers could refine treatment choice based on a better identification of men at risk of biochemical recurrence (BCR) following therapy. The urokinase plasminogen activator receptor (uPAR) system is a promising biomarker of aggressiveness in many cancers. The predictive value of uPAR after curatively intended treatment for PCa remains to be elucidated. This was a prospective evaluation of uPAR analysis in men with prostate cancer (Copenhagen uPAR prostate cancer (CuPCA) database). Risk of BCR following RP was analyzed using cumulative incidences with competing risk and tested with Gray’s test. Associations between quartile groups of uPAR levels and BCR were assessed with uni- and multivariate Cox proportional hazards. In total, 532 men were included. With more advanced tumor stage, Gleason score (GS), and prostate-specific antigen (PSA) the uPAR I–III + II–III plasma levels increased. Quartile levels of plasma uPAR I–III, I–III + II–III showed no significant association between the risk of BCR and the plasma uPAR levels in uni- and multivariate analysis. Despite increased levels of uPAR I–III + II–III in advanced tumor stage, intact and cleaved uPAR levels were not associated with BCR and are not predictive biomarkers for BCR following curatively intended treatment of PCa. It is unlikely that further studies of uPAR in RP treated patients is needed.
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Stahl, A., and B. M. Mueller. "The urokinase-type plasminogen activator receptor, a GPI-linked protein, is localized in caveolae." Journal of Cell Biology 129, no. 2 (April 15, 1995): 335–44. http://dx.doi.org/10.1083/jcb.129.2.335.
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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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Hau, Andrew M., Andrew Gilder, Jing-jing Hu, Steven L. Gonias, and Donna E. Hansel. "uPAR and mTORC2 as coupled targets for therapeutics development in bladder cancer." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 447. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.447.
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447 Background: Bladder cancer currently ranks as the fifth most common and the single most expensive cancer to manage in the United States. Although it is established that invasive behavior is a major predictor of diminished outcomes for patients with bladder cancer, the molecular mechanisms governing bladder cancer cell invasion are not well understood. The urokinase receptor (uPAR) and mammalian target of rapamycin complex 2 (mTORC2) represent two powerful pro-invasion candidates that have increased expression in high-grade, invasive bladder cancer, though the former has not been characterized in detail in bladder cancer. Therefore, the aims of this study are to characterize the uPAR signaling network and delineate the signaling interplay between mTORC2 and uPAR in bladder cancer. Methods: Using immunoblot and RT-qPCR analyses, we evaluated uPAR expression in a panel of immortalized bladder cancer cell lines: UROtsa, RT4, UMUC3, T24 and J82. uPAR influence on mTORC1 and mTORC2 signaling was determined by immunoblot analysis following targeted gene-silencing of uPAR using siRNA. Additionally, the effects of uPAR knockdown on cell migration and invasion were investigated using modified scratch-wound migration and transwell invasion assays. Lastly, signaling interplay between uPAR and mTORC2 was investigated by evaluating the effects of uPAR and mTORC2 silencing on Rac1 activity. Results: uPAR knockdown in a subset (T24 and J82) of invasive bladder cancer cell lines inhibited mTORC2, but not mTORC1, activity as measured by P-AKT S473 and P-S6 levels. We found that uPAR silencing in T24 and J82 cells resulted in significant reductions in cell migration and invasion through Matrigel. This is likely attributed to inhibition of Rac1 and decreased lamellipodia formation. Conclusions: Collectively, our results identify uPAR and mTORC2 as major regulators of bladder cancer cell invasion and that these two systems are linked through Rac1. Further investigation of uPAR and mTORC2 inhibition using uPAR-targeting antibodies and mTOR inhibitors in an in vivo mouse model of bladder cancer will determine if these signaling pathways are therapeutically beneficial for the treatment of bladder cancer.
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Przybylowska, Karolina, Janusz Szemraj, Andrzej Kulig, Adam Dziki, Joanna Ulanska, and Janusz Blasiak. "Antigen levels of urokinase-type plasminogen activator receptor and its gene polymorphism related to microvessel density in colorectal cancer." Acta Biochimica Polonica 55, no. 2 (May 29, 2008): 357–63. http://dx.doi.org/10.18388/abp.2008_3083.
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We determined the distribution of genotypes and frequencies of alleles of the (CA)(n) repeat polymorphism in intron 3 of the urokinase plasminogen activator receptor (uPAR) gene, uPAR antigen levels and microvessel density (MVD) in tumour and distant mucosa samples from 52 patients with colorectal cancer. The uPAR level was higher for patients with high MVD comparing to patients with lower MVD which may suggest that uPAR can be correlated with progression of colorectal cancer. The significant relationship between the high MVD and uPAR antigen level appeared to be independent of the (CA)(n) repeat polymorphism because no differences in the level of uPAR antigen between carriers of alleles were found. The received results, indicate that uPAR might be considered as a target in colorectal cancer patients' therapy.
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Leduc, Dominique, Nathalie Beaufort, Sophie de Bentzmann, Jean-Claude Rousselle, Abdelkader Namane, Michel Chignard, and Dominique Pidard. "The Pseudomonas aeruginosa LasB Metalloproteinase Regulates the Human Urokinase-Type Plasminogen Activator Receptor through Domain-Specific Endoproteolysis." Infection and Immunity 75, no. 8 (May 21, 2007): 3848–58. http://dx.doi.org/10.1128/iai.00015-07.
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ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen in human lungs, where its secretable LasB metalloproteinase can be a virulence factor. The urokinase-type plasminogen activator receptor (uPAR) participates in pericellular proteolysis and the adherence/migration of epithelial cells and leukocytes recruited during infection and shows functional regulation by various proteinases via limited endoproteolysis occurring within its three domains (D1 to D3). We thus examined the proteolytic activity of LasB on uPAR by using recombinant uPAR as well as uPAR-expressing, human monocytic, and bronchial epithelial cell lines. Protein immunoblotting and flow immunocytometry using a panel of domain-specific anti-uPAR antibodies showed that LasB is able to cleave uPAR both within the sequence linking D1 to D2 and at the carboxy terminus of D3. Comparison of LasB-producing and LasB-deficient bacterial strains indicated that LasB is entirely responsible for the uPAR cleavage ability of P. aeruginosa. Based on amino-terminal protein microsequencing and mass spectrometry analysis of the cleavage of peptides mimicking the uPAR sequences targeted by LasB, cleavage sites were determined to be Ala84-Val85 and Thr86-Tyr87 (D1-D2) and Gln279-Tyr280 (D3). Such a dual cleavage of uPAR led to the removal of amino-terminal D1, the generation of a truncated D2D3 species, and the shedding of D2D3 from cells. This proteolytic processing of uPAR was found to (i) drastically reduce the capacity of cells to bind urokinase and (ii) abrogate the interaction between uPAR and the matrix adhesive protein vitronectin. The LasB proteinase is thus endowed with a high potential for the alteration of uPAR expression and functioning on inflammatory cells during infections by P. aeruginosa.
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Blasi, Francesco, and Peter Carmeliet. "uPAR: a versatile signalling orchestrator." Nature Reviews Molecular Cell Biology 3, no. 12 (December 2002): 932–43. http://dx.doi.org/10.1038/nrm977.
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Hirsch, Emilio. "Two signalling hands for uPAR." Thrombosis and Haemostasis 109, no. 02 (2013): 179. http://dx.doi.org/10.1160/th13-01-0001.
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Blasi, Francesco, and Nicolai Sidenius. "Efferocytosis: another function of uPAR." Blood 114, no. 4 (July 23, 2009): 752–53. http://dx.doi.org/10.1182/blood-2009-05-220657.
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Piguet, Pierre Francois, Chen Da Laperrousaz, Christian Vesin, Fabienne Tacchini-Cottier, Giorgio Senaldi, and Georges Emile Grau. "Delayed Mortality and Attenuated Thrombocytopenia Associated with Severe Malaria in Urokinase- and Urokinase Receptor-Deficient Mice." Infection and Immunity 68, no. 7 (July 1, 2000): 3822–29. http://dx.doi.org/10.1128/iai.68.7.3822-3829.2000.
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ABSTRACT We explored the role of urokinase and tissue-type plasminogen activators (uPA and tPA), as well as the uPA receptor (uPAR; CD87) in mouse severe malaria (SM), using genetically deficient (−/−) mice. The mortality resulting from Plasmodium berghei ANKA infection was delayed in uPA−/− and uPAR−/−mice but was similar to that of the wild type (+/+) in tPA−/− mice. Parasitemia levels were similar in uPA−/−, uPAR−/−, and +/+ mice. Production of tumor necrosis factor, as judged from the plasma level and the mRNA levels in brain and lung, was markedly increased by infection in both +/+ and uPAR−/− mice. Breakdown of the blood-brain barrier, as evidenced by the leakage of Evans Blue, was similar in +/+ and uPAR−/− mice. SM was associated with a profound thrombocytopenia, which was attenuated in uPA−/− and uPAR−/− mice. Administration of aprotinin, a plasmin antagonist, also delayed mortality and attenuated thrombocytopenia. Platelet trapping in cerebral venules or alveolar capillaries was evident in +/+ mice but absent in uPAR−/− mice. In contrast, macrophage sequestration in cerebral venules or alveolar capillaries was evident in both +/+ and uPAR−/− mice. Polymorphonuclear leukocyte sequestration in alveolar capillaries was similar in +/+ and uPAR−/− mice. These results demonstrate that the uPAR deficiency attenuates the severity of SM, probably by its important role in platelet kinetics and trapping. These results therefore suggest that platelet sequestration contributes to the pathogenesis of SM.