Disease relevance of PLAU

• Urokinase-plasminogen activator (PLAU) was suggested to be involved in the pathogenesis of elastin and collagen degradation in arterial aneurysm [1].
• The role of PLAU genetic variant in mitral valve prolapse (MVP) has not been studied [1].
• This evidence provides a direct link between uPA- and PDGF D-mediated cell signaling, which may contribute to the progression of prostate cancer [2].
• Hypoxia increases uPA association and the angiogenic response of human endothelial cells in a fibrin matrix; the increase in the uPA receptor is an important determinant in this process [3].
• Our results support the hypothesis that the uPA system probably is of general importance for prognosis of patients with malignant disease, indicating an individual tumor's capacity for invasion and metastasis [4].

Psychiatry related information on PLAU

• The urokinase-plasminogen activator (PLAU) gene is not associated with late onset Alzheimer's disease [5].
• Only individual patients with severe AIDS dementia complex had increased levels of uPA (but not PAI-1) which fell upon initiation of antiretroviral therapy [6].
• We investigated the expression of MMP-9, uPA, and uPAR in post-mortem brains from patients with Alzheimer's disease (AD) and those with vascular dementia (VD) [7].
• To investigate the role of the uPA/uPAR system in the pathophysiology of acquired immunodeficiency syndrome dementia complex (ADC), we measured soluble uPAR (suPAR) levels in cerebrospinal fluid (CSF) and plasma from human immunodeficiency virus (HIV)-1-infected patients and controls [8].
• These data indicate that uPA is produced by human preimplantation embryos and may play a role in early human development and embryo implantation [9].

High impact information on PLAU

• We found that genes with binding sites for the archetypal cancer transcription factor, E2F, were disproportionately overexpressed in a wide variety of cancers, whereas genes with binding sites for other transcription factors, such as Myc-Max, c-Rel and ATF, were disproportionately overexpressed in specific cancer types [10].
• We concluded that breaching of the vascular wall is a rate-limiting step for intravasation, and consequently for metastasis, and that cooperation between uPA/uPAR and MMP-9 is required to complete this step [11].
• Spontaneous intestinal and intra-abdominal bleeding was observed in a high percentage of newborn transgenic mice carrying the murine urokinase-type plasminogen activator (uPA) gene linked to the albumin enhancer/promoter [12].
• These hemorrhagic events were directly related to transgene expression in the liver and the development of high plasma uPA levels [12].
• A specific member of the ATF transcription factor family can mediate transcription activation by the adenovirus E1a protein [13].

Chemical compound and disease context of PLAU

• In conclusion, uPA, uPAR, and PAI-1, components of the urokinase system, are predictive for the efficacy of tamoxifen therapy in patients treated for recurrent breast cancer [14].
• We have recently reported that tyrosine kinase, p56(lck) regulates cell motility and nuclear factor kappaB-mediated secretion of urokinase-type plasminogen activator (uPA) through tyrosine phosphorylation of IkappaBalpha following hypoxia/reoxygenation (Mahabeleshwar, G. H., and Kundu, G. C. (2003) J. Biol. Chem. 278, 52598-52612) [15].
• We have recently reported that osteopontin (OPN) stimulates cell motility and nuclear factor kappaB-mediated secretion of urokinase-type plasminogen activator (uPA) through phosphatidylinositol 3-kinase/Akt signaling pathways in breast cancer cells (Das, R., Mahabeleshwar, G. H., and Kundu, G. C. (2003) J. Biol. Chem. 278, 28593-28606) [16].
• The serine protease urokinase (uPA) is a potent chemoattractant for leukocytes that may be involved in the pathogenesis of severe forms of allergic conjunctivitis such as vernal keratoconjunctivitis (VKC) [17].
• In order to elucidate the possible role of the Pro121Leu exchange in uPA and the Ala/Thr variants in the signal sequence of PAI-1 in the development and/or progression of human ovarian cancer, we studied the presence of these mutants or variants in a series of 22 ovarian cancer tissues [18].

Biological context of PLAU

• We evaluated single nucleotide polymorphisms (SNPs) in PLAU for association with Abeta42 and LOAD [19].
• PLAU SNP haplotypes associated significantly with plasma Abeta42 in 10 extended LOAD families [19].
• One gene (PLAU) showed cancer cell-specific methylation that did not correlate well with expression status [20].
• Invasion was assessed on Day 6, explants were harvested for analysis of apoptosis and proliferation, and medium was stored for analysis of PLAU system components by ELISA and casein zymography [21].
• Among the most strongly up-regulated genes at that time were the urokinase plasminogen activator (PLAU) and its receptor (PLAUR), a pleiotropic system involved in many biological processes, including chemotaxis and inflammation [22].

Anatomical context of PLAU

• By size fractionation of monocyte lysate and affinity isolation on its natural ligand uPA, we demonstrate uPA-R as a component of a receptor complex of relatively large size [23].
• U937 cells were incubated at 4 degrees C with labeled uPA-PAI-1 (and other ligands), the temperature then raised to 37 degrees C and the fate of the ligand followed for 3 h thereafter [24].
• In a uPAR-deficient cell line (LM-TK-), suPAR increased uPA binding up to 10-fold, whereas the truncated receptor lacking the amino-terminal uPA-binding domain was ineffective [25].
• Primary cultures of human endothelial cells release very little urokinase-type plasminogen activator (u-PA) [26].
• In this study, we used human peripheral blood neutrophils and transfected cells expressing alpha(M)beta(2), uPAR, or both receptors to show that the integrin can directly interact with urokinase (uPA) [27].

Associations of PLAU with chemical compounds

• One of the SNPs analyzed was a missense C/T polymorphism in exon 6 of PLAU (PLAU_1=rs2227564), which causes a proline to leucine change (P141L) [19].
• PLAU receptor and plasminogen activator inhibitor-2 protein levels were increased and PLAU activity decreased in these cultures [21].
• Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)) [28].
• This activity was blocked by receptor-associated protein and not observed with uPA-PAI-1(R76E) complex, demonstrating the importance of the VLDLr. uPA promoted the growth of other cells in which ERK phosphorylation was sustained, including beta3 integrin overexpressing MCF-7 cells and HT 1080 cells [29].
• The degradation of the uPA-PAI-1 complex is preceded by internalization and is inhibited by chloroquine, an inhibitor of lysosomal protein degradation [24].

Physical interactions of PLAU

• We have now investigated whether PAI-1 can bind and inhibit receptor-bound uPA [30].
• Thus, recognition of uPA by alpha(M)beta(2) allows for formation of a multicontact trimolecular complex, in which a single uPA ligand may bind simultaneously to both uPAR and alpha(M)beta(2) [27].
• The high-affinity binding of tPA to VSMCs resulted in an eightfold greater potential for plasmin generation than the binding of uPA, with this difference increasing to 15-fold after thrombin stimulation of the cells due to a 1.8-fold increase in tPA binding [31].
• Moreover, VN-mediated binding of the uPA/suPAR-complex led to a fivefold increase in plasminogen activator activity [25].
• In these plasma samples uPA-PCI complexes were present in a concentration corresponding to 21% to 25% of inactive uPA antigen [32].

Enzymatic interactions of PLAU

• Urokinase plasminogen activator (uPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin [33].
• However, the specificity of the inhibitory reaction with tPA and uPA was notably higher than that for the substrate reaction catalyzed by elastase. pH dependences of k(lim) and K(0.5) obtained for tPA revealed an additional ionizable group (pKa, 6.0-6.2) affecting the reaction [34].
• MAPK and JNK transduction pathways can phosphorylate Sp1 to activate the uPA minimal promoter element and endogenous gene transcription [35].
• The urokinase-type plasminogen activator (uPA) is able to cleave its cell surface receptor (uPAR) anchored to the cell membrane through a glycophosphatidylinositol tail [36].
• We found that Vn is indeed selectively phosphorylated by CK2 and that this phosphorylation is uPA-regulated in VSMC [37].

Co-localisations of PLAU

• With this technique uPAR colocalizes with uPA in 71% of labeled granules [38].
• Part of the tPA was detected in the extracellular space and colocalized with fibrin deposits. uPA antigen and mRNA were detected in association with the intimal macrophages and SMCs [39].

Regulatory relationships of PLAU

• Our results demonstrate that PAI-1 may regulate uPA-initiated cell signaling by a mechanism that requires VLDLr recruitment [29].
• The uPA-induced increase in MCF-7 cell migration was observed selectively on vitronectin-coated surfaces and was mediated by a beta1-integrin (probably alphaVbeta1) and alphaVbeta5 [40].
• Inactivation of protein-tyrosine phosphatase SHP-2 inhibits both basal and uPA-induced p53 expression [33].
• The rate of transmigration was consistently higher for u-PA-expressing cells than for t-PA-expressing cells [41].
• Both IL-1beta and TNF-alpha induced a significant decrease in uPA expression in PBF, whereas bFGF induced a slight increase in both HJF and PBF [42].
• The N-terminal fragment of uPA, which binds to uPAR, but lacks the catalytic site, failed to induce MMP-1 production, indicating that uPA-stimulated MMP-1 synthesis was plasmin dependent [43].

Other interactions of PLAU

• This function of uPAR is not dependent upon its occupancy with uPA, which negatively influences adhesion [44].
• RESULTS: Eight of 14 CP samples showed concomitant increased expression (P < 0.001) of uPA (5.2-fold), uPAR (5.9-fold), and TGF-beta 1 (8.8-fold) messenger RNA (mRNA) compared with normal controls [45].
• Plasminogen activator inhibitor 1 (PAI-1) is a major inhibitor of urokinase-type plasminogen activator (uPA) [29].
• During pregnancy, the t-PA and prourokinase (u-PA) antigen concentrations increased 50% and 200%, respectively, whereas the plasminogen and alpha 2-antiplasmin levels remained constant [46].
• In contrast to TNF-alpha-induced PAI-1 production, the transcription and synthesis of urokinase-type plasminogen activator (u-PA) was not inhibited by genistein [47].

Analytical, diagnostic and therapeutic context of PLAU

• The T4065C and T3995C polymorphisms of the PLAU gene were identified by polymerase chain reaction (PCR)-based restriction analysis [1].
• We, therefore, performed a case-controlled study investigating the possible relation between the PLAU gene polymorphisms and risk of MVP in Taiwan Chinese. METHODS: We studied 100 patients with MVP diagnosed by echocardiography and 106 age- and sex-matched normal control subjects [1].
• PAI-1 also binds to, and inhibits the activity of, receptor-bound uPA in U937 cells, as shown in U937 cells by a caseinolytic plaque assay [30].
• High levels of uPA, uPAR, and PAI-1 predicted a shorter progression-free survival (PFS) on tamoxifen in an analysis of the first 9 months of therapy [14].
• Urokinase-plasminogen activator receptors (u-PAR) were measured by radioligand binding, cell cross-linking, immunoassay, and RNAse protection assay. u-PA and plasminogen activator inhibitors (PAIs) expression and activities were analyzed by zymography, immunoassay, and RNase protection assay [48].

References