Disease relevance of Plaur

• HGF/SF induces the expression of urokinase plasminogen activator (uPA) and the uPA receptor (uPAR), important mediators of cell invasion and metastasis [1].
• Adenovirus-mediated delivery of antisense gene to urokinase-type plasminogen activator receptor suppresses glioma invasion and tumor growth [2].
• In contrast, uPAR-/- mice had a delayed, less acute disease reflected in delayed infiltration of inflammatory cells [3].
• These mice provide a means to test the proposed function of uPA/uPAR in wound repair, atherogenesis, and tumor cell invasion in vivo [4].
• Thus, the plasminogen activator system can modulate both inflammatory and degenerative events in the CNS through the respective effects of tPA and uPAR on fibrinolysis and cell adhesion/migration, manipulation of which may have therapeutic implications for multiple sclerosis [3].

Psychiatry related information on Plaur

• UPAR(-/-) MEFs grew faster at low serum, produced more colonies in agar and produced tumors in vivo in nude mice with a lower latency period [5].

High impact information on Plaur

• Overexpression of CDC91L1 also resulted in upregulation of the urokinase receptor (uPAR), a GPI-anchored protein, and in turn increased STAT-3 phosphorylation in bladder cancer cells [6].
• Moreover, uPAR ligation differentially modulates leukocyte adhesion to endothelium and provides novel targets for therapeutic strategies in inflammation-related vascular pathologies [7].
• RESULTS: In vitro, DTAT was highly potent and selective in killing uPAR-expressing glioblastoma cells (U118MG, U373MG, and U87MG) and human umbilical vein endothelial cells [8].
• Mice homozygously deficient for the urokinase-type plasminogen activator (u-PA) receptor (u-PAR-1-) were generated by homologous recombination in D3, embryonic stem cells [9].
• Inactivation of u-PAR was confirmed by the absence of binding of rabbit anti-murine u-PAR or of an aminoterminal fragment of murine u-PA (mu-PA.1-48) to u-PAR-1- embryonic fibroblasts and macrophages. u-PAR-1- mice displayed normal lysis of a murine plasma clot injected via the jugular vein [9].

Chemical compound and disease context of Plaur

• 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 [10].
• OBJECTIVES: The key objective of the study was to determine the single and multiple dose toxicity and efficacy of Bismuth-213 labeled PAI2 based targeted alpha therapy by selectively targeting uPA and uPAR in regressing prostate cancer in a nude mouse model [11].
• Pimonidazole was used as a hypoxia marker, and hypoxia and uPAR expression were detected by immunohistochemistry [12].
• An important factor implicated in tumor cell predisposition for invasion and metastasis is the malignancy-related upregulation of urokinase plasminogen activator receptor (uPAR). uPAR signals by activating different tyrosine kinases in different cells [13].
• Urokinase-type plasminogen activator receptor plays a role in neutrophil migration during lipopolysaccharide-induced peritoneal inflammation but not during Escherichia coli-induced peritonitis [14].

Biological context of Plaur

• This is the first demonstration that uPAR has a physiological role in fibrinolysis [15].
• We show that fibroblast growth factor-2 (FGF-2) stimulates TTB cell migration and promotes polarization of uPAR at the leading edge of migrating cells [16].
• Thus, in the absence of other challenging factors such as infection, injury, or other functional deficits, uPAR deficiency does not compromise fertility, development, or hemostasis [4].
• In the present study, we provide experimental evidence that consolidates and further develops this model using data from a comprehensive alanine scanning mutagenesis of uPAR combined with low resolution distance constraints defined within the complex using chemical cross-linkers as molecular rulers [17].
• These results demonstrate that the uPAR deficiency attenuates the severity of SM, probably by its important role in platelet kinetics and trapping [18].

Anatomical context of Plaur

• High-level expression of uPAR has been correlated with high-grade glioma cell lines and tumors We report here that down-regulating uPAR levels by antisense strategy using an adenovirus construct (Ad-uPAR) inhibited glioma invasion in Matrigel and spheroid in vitro models. sc [2].
• Transcripts for tissue inhibitors of metalloproteinases (TIMP-1,-2,-3) and uPA receptor were detected throughout pre- and peri-implantation development whilst MMP-9 and uPA mRNAs were first detected in peri-implantation blastocysts associated with the invasive phase of implantation [19].
• In addition, activated peritoneal macrophages collected from uPAR-/- mice failed to promote plasminogen activation in vitro [4].
• Compared with uPAR+/+ cells, uPAR-/- kidney fibroblasts were hyperproliferative [20].
• Polymorphonuclear leukocyte sequestration in alveolar capillaries was similar in +/+ and uPAR(-/-) mice [18].

Associations of Plaur with chemical compounds

• The genomic sequences comprising exon 2 through 5 of the u-PAR gene were replaced by the neomycin resistance gene, resulting in inactivation of both u-PAR splice variants [9].
• This complete alanine scanning of uPAR highlighted the involvement of 20 surface-exposed side chains in this interaction [17].
• Breakdown of the blood-brain barrier, as evidenced by the leakage of Evans Blue, was similar in +/+ and uPAR(-/-) mice [18].
• Consistent with an increased platelet production, platelets from uPAR-/- mice had a higher RNA content, as seen by Propidium Iodide (PI) labeling and FACS analysis [21].
• In contrast, the blood pressure of urokinase receptor knockout (uPAR(-/-)) mice and the response of their isolated aortic rings to phenylephrine were normal, indicating that the effect of uPA on vascular contraction is independent of uPAR [22].

Physical interactions of Plaur

• Immunoelectron microscopy of injured arteries in vivo revealed that u-PA was bound on the cell surface of u-PAR+/+ cells, whereas it was present in the pericellular space around u-PAR-/- cells [23].

Regulatory relationships of Plaur

• The mitogenic and chemotactic responses of bFGF were specifically inhibited in u-PAR-deficient cells or in wild-type SMC, cultured in the presence of antibodies to u-PAR [24].
• These uPA-induced signaling events are not mediated by uPAR, but mediated by unidentified, lower-affinity receptors for the uPA kringle [25].
• The urokinase-type plasminogen activator and its receptor (u-PAR) contribute to prostate cancer metastases by promoting extracellular matrix degradation and growth factor activation [26].

Other interactions of Plaur

• We report a comparative study of animals with individual and combined deficits in uPAR and tPA and show that these proteins are complementary fibrinolytic factors in mice [15].
• These results do not argue in favor of a role for uPAR-mediated signaling in our experimental model; rather, they demonstrate an essential, dose-dependent, requirement for plasminogen in uPA-mediated tissue alterations [27].
• This study examined the role of uPAR and its co-receptor LDL receptor-related protein (LRP) in the regulation of kidney fibroblast proliferation and extracellular signal-regulated kinase (ERK) signaling [20].
• In adult testes, PCI and uPAR immunoreactivities were also present in Leydig cells [28].
• TGF-beta mRNA level within the bone marrow was also significantly increased in uPAR-/- mice [21].

Analytical, diagnostic and therapeutic context of Plaur

• There was no indication of loss of fetal animals based on the Mendelian pattern of transmission of the mutant uPAR gene. uPAR-/- mice carried no detectable uPAR in lung, spleen, and other tissues when measured both immunologically by Western blot analysis and functionally by ligand cross-linking analyses [4].
• The kinetic rate constants for the interaction between pro-uPA and 244 purified uPAR mutants with single-site replacements were determined by surface plasmon resonance [17].
• By in situ hybridization, uPAR mRNA transcripts were detected in renal tubules and interstitial cells of the obstructed uPAR+/+ kidneys [29].
• Purification of the two mouse u-PAR variant proteins by diisopropylfluorophosphate-inactivated mouse u-PA-Sepharose affinity chromatography yielded two silver-stained bands when analysed by SDS/PAGE, corresponding in electrophoretic mobility to those seen by ligand-blotting analysis.(ABSTRACT TRUNCATED AT 400 WORDS)[30]
• In those in which uPA, uPAR, and PAI-1 were all positive staining, stronger cancer invasiveness and higher mortality were found (P<0.05 vs. patients with all negative staining) [31].

References