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Gene Review

PLAU  -  plasminogen activator, urokinase

Homo sapiens

Synonyms: ATF, BDPLT5, QPD, U-plasminogen activator, UPA, ...
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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


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


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].


  1. Association between urokinase-plasminogen activator gene T4065C polymorphism and risk of mitral valve prolapse. Chou, H.T., Chen, Y.T., Wu, J.Y., Tsai, F.J. International journal of cardiology. (2004) [Pubmed]
  2. Platelet-derived growth factor D is activated by urokinase plasminogen activator in prostate carcinoma cells. Ustach, C.V., Kim, H.R. Mol. Cell. Biol. (2005) [Pubmed]
  3. Urokinase receptor expression on human microvascular endothelial cells is increased by hypoxia: implications for capillary-like tube formation in a fibrin matrix. Kroon, M.E., Koolwijk, P., van der Vecht, B., van Hinsbergh, V.W. Blood (2000) [Pubmed]
  4. Tumor-associated proteolysis and prognosis: new functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system. Heiss, M.M., Babic, R., Allgayer, H., Gruetzner, K.U., Jauch, K.W., Loehrs, U., Schildberg, F.W. J. Clin. Oncol. (1995) [Pubmed]
  5. The urokinase-plasminogen activator (PLAU) gene is not associated with late onset Alzheimer's disease. Bagnoli, S., Tedde, A., Cellini, E., Rotondi, M., Nacmias, B., Sorbi, S. Neurogenetics (2005) [Pubmed]
  6. Evaluation of cerebrospinal fluid uPA, PAI-1, and soluble uPAR levels in HIV-infected patients. Sporer, B., Koedel, U., Popp, B., Paul, R., Pfister, H.W. J. Neuroimmunol. (2005) [Pubmed]
  7. Expression of matrix metalloproteinase-9 and urinary-type plasminogen activator in Alzheimer's disease brain. Asahina, M., Yoshiyama, Y., Hattori, T. Clin. Neuropathol. (2001) [Pubmed]
  8. The urokinase receptor is overexpressed in the AIDS dementia complex and other neurological manifestations. Cinque, P., Nebuloni, M., Santovito, M.L., Price, R.W., Gisslen, M., Hagberg, L., Bestetti, A., Vago, G., Lazzarin, A., Blasi, F., Sidenius, N. Ann. Neurol. (2004) [Pubmed]
  9. Expression of urokinase-type plasminogen activator in human preimplantation embryos. Khamsi, F., Armstrong, D.T., Zhang, X. Mol. Hum. Reprod. (1996) [Pubmed]
  10. Mining for regulatory programs in the cancer transcriptome. Rhodes, D.R., Kalyana-Sundaram, S., Mahavisno, V., Barrette, T.R., Ghosh, D., Chinnaiyan, A.M. Nat. Genet. (2005) [Pubmed]
  11. Requirement for specific proteases in cancer cell intravasation as revealed by a novel semiquantitative PCR-based assay. Kim, J., Yu, W., Kovalski, K., Ossowski, L. Cell (1998) [Pubmed]
  12. Neonatal bleeding in transgenic mice expressing urokinase-type plasminogen activator. Heckel, J.L., Sandgren, E.P., Degen, J.L., Palmiter, R.D., Brinster, R.L. Cell (1990) [Pubmed]
  13. A specific member of the ATF transcription factor family can mediate transcription activation by the adenovirus E1a protein. Liu, F., Green, M.R. Cell (1990) [Pubmed]
  14. Urokinase-type plasminogen activator system in breast cancer: association with tamoxifen therapy in recurrent disease. Meijer-van Gelder, M.E., Look, M.P., Peters, H.A., Schmitt, M., Brünner, N., Harbeck, N., Klijn, J.G., Foekens, J.A. Cancer Res. (2004) [Pubmed]
  15. Tyrosine kinase, p56lck-induced cell motility, and urokinase-type plasminogen activator secretion involve activation of epidermal growth factor receptor/extracellular signal regulated kinase pathways. Mahabeleshwar, G.H., Das, R., Kundu, G.C. J. Biol. Chem. (2004) [Pubmed]
  16. Osteopontin induces AP-1-mediated secretion of urokinase-type plasminogen activator through c-Src-dependent epidermal growth factor receptor transactivation in breast cancer cells. Das, R., Mahabeleshwar, G.H., Kundu, G.C. J. Biol. Chem. (2004) [Pubmed]
  17. Urokinase plasminogen activator, uPa receptor, and its inhibitor in vernal keratoconjunctivitis. Leonardi, A., Brun, P., Sartori, M.T., Cortivo, R., Dedominicis, C., Saggiorato, G., Abatangelo, G., Secchi, A.G. Invest. Ophthalmol. Vis. Sci. (2005) [Pubmed]
  18. Mutational analysis of the genes encoding urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in advanced ovarian cancer. Türkmen, B., Schmitt, M., Schmalfeldt, B., Trommler, P., Hell, W., Creutzburg, S., Graeff, H., Magdolen, V. Electrophoresis (1997) [Pubmed]
  19. Elevated amyloid beta protein (Abeta42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene. Ertekin-Taner, N., Ronald, J., Feuk, L., Prince, J., Tucker, M., Younkin, L., Hella, M., Jain, S., Hackett, A., Scanlin, L., Kelly, J., Kihiko-Ehman, M., Neltner, M., Hersh, L., Kindy, M., Markesbery, W., Hutton, M., de Andrade, M., Petersen, R.C., Graff-Radford, N., Estus, S., Brookes, A.J., Younkin, S.G. Hum. Mol. Genet. (2005) [Pubmed]
  20. Identification of novel target genes by an epigenetic reactivation screen of renal cancer. Ibanez de Caceres, I., Dulaimi, E., Hoffman, A.M., Al-Saleem, T., Uzzo, R.G., Cairns, P. Cancer Res. (2006) [Pubmed]
  21. Low oxygen concentrations inhibit trophoblast cell invasion from early gestation placental explants via alterations in levels of the urokinase plasminogen activator system. Lash, G.E., Otun, H.A., Innes, B.A., Bulmer, J.N., Searle, R.F., Robson, S.C. Biol. Reprod. (2006) [Pubmed]
  22. Distinct gene subsets are induced at different time points after human respiratory syncytial virus infection of A549 cells. Martínez, I., Lombardía, L., García-Barreno, B., Domínguez, O., Melero, J.A. J. Gen. Virol. (2007) [Pubmed]
  23. Urokinase plasminogen activator receptor, beta 2-integrins, and Src-kinases within a single receptor complex of human monocytes. Bohuslav, J., Horejsí, V., Hansmann, C., Stöckl, J., Weidle, U.H., Majdic, O., Bartke, I., Knapp, W., Stockinger, H. J. Exp. Med. (1995) [Pubmed]
  24. Receptor-mediated internalization and degradation of urokinase is caused by its specific inhibitor PAI-1. Cubellis, M.V., Wun, T.C., Blasi, F. EMBO J. (1990) [Pubmed]
  25. Vitronectin concentrates proteolytic activity on the cell surface and extracellular matrix by trapping soluble urokinase receptor-urokinase complexes. Chavakis, T., Kanse, S.M., Yutzy, B., Lijnen, H.R., Preissner, K.T. Blood (1998) [Pubmed]
  26. Tumor necrosis factor induces the production of urokinase-type plasminogen activator by human endothelial cells. van Hinsbergh, V.W., van den Berg, E.A., Fiers, W., Dooijewaard, G. Blood (1990) [Pubmed]
  27. Convergence of the adhesive and fibrinolytic systems: recognition of urokinase by integrin alpha Mbeta 2 as well as by the urokinase receptor regulates cell adhesion and migration. Pluskota, E., Soloviev, D.A., Plow, E.F. Blood (2003) [Pubmed]
  28. Towards compendia of negative genetic association studies: an example for Alzheimer disease. Blomqvist, M.E., Reynolds, C., Katzov, H., Feuk, L., Andreasen, N., Bogdanovic, N., Blennow, K., Brookes, A.J., Prince, J.A. Hum. Genet. (2006) [Pubmed]
  29. Plasminogen activator inhibitor 1 functions as a urokinase response modifier at the level of cell signaling and thereby promotes MCF-7 cell growth. Webb, D.J., Thomas, K.S., Gonias, S.L. J. Cell Biol. (2001) [Pubmed]
  30. Accessibility of receptor-bound urokinase to type-1 plasminogen activator inhibitor. Cubellis, M.V., Andreasen, P., Ragno, P., Mayer, M., Danø, K., Blasi, F. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  31. Vascular smooth muscle cells potentiate plasmin generation by both urokinase and tissue plasminogen activator-dependent mechanisms: evidence for a specific tissue-type plasminogen activator receptor on these cells. Ellis, V., Whawell, S.A. Blood (1997) [Pubmed]
  32. Complex formation between urokinase and plasma protein C inhibitor in vitro and in vivo. Geiger, M., Huber, K., Wojta, J., Stingl, L., Espana, F., Griffin, J.H., Binder, B.R. Blood (1989) [Pubmed]
  33. Induction of p53 by urokinase in lung epithelial cells. Shetty, S., Gyetko, M.R., Mazar, A.P. J. Biol. Chem. (2005) [Pubmed]
  34. Protonation state of a single histidine residue contributes significantly to the kinetics of the reaction of plasminogen activator inhibitor-1 with tissue-type plasminogen activator. Komissarov, A.A., Declerck, P.J., Shore, J.D. J. Biol. Chem. (2004) [Pubmed]
  35. MAPK and JNK transduction pathways can phosphorylate Sp1 to activate the uPA minimal promoter element and endogenous gene transcription. Benasciutti, E., Pagès, G., Kenzior, O., Folk, W., Blasi, F., Crippa, M.P. Blood (2004) [Pubmed]
  36. The cleavage of the urokinase receptor regulates its multiple functions. Montuori, N., Carriero, M.V., Salzano, S., Rossi, G., Ragno, P. J. Biol. Chem. (2002) [Pubmed]
  37. Urokinase-dependent human vascular smooth muscle cell adhesion requires selective vitronectin phosphorylation by ectoprotein kinase CK2. Stepanova, V., Jerke, U., Sagach, V., Lindschau, C., Dietz, R., Haller, H., Dumler, I. J. Biol. Chem. (2002) [Pubmed]
  38. Subcellular distribution of urokinase and urokinase receptor in human neutrophils determined by immunoelectron microscopy. Pedersen, T.L., Plesner, T., Horn, T., Høyer-Hansen, G., Sørensen, S., Hansen, N.E. Ultrastructural pathology. (2000) [Pubmed]
  39. Plasminogen activator expression in human atherosclerotic lesions. Lupu, F., Heim, D.A., Bachmann, F., Hurni, M., Kakkar, V.V., Kruithof, E.K. Arterioscler. Thromb. Vasc. Biol. (1995) [Pubmed]
  40. Myosin light chain kinase functions downstream of Ras/ERK to promote migration of urokinase-type plasminogen activator-stimulated cells in an integrin-selective manner. Nguyen, D.H., Catling, A.D., Webb, D.J., Sankovic, M., Walker, L.A., Somlyo, A.V., Weber, M.J., Gonias, S.L. J. Cell Biol. (1999) [Pubmed]
  41. Plasminogen activators play an essential role in extracellular-matrix invasion by lymphoblastic T cells. Reiter, L.S., Spertini, O., Kruithof, E.K. Int. J. Cancer (1997) [Pubmed]
  42. Regulation of collagenase, stromelysin, and urokinase-type plasminogen activator in primary pterygium body fibroblasts by inflammatory cytokines. Solomon, A., Li, D.Q., Lee, S.B., Tseng, S.C. Invest. Ophthalmol. Vis. Sci. (2000) [Pubmed]
  43. Urokinase-type plasminogen activator stimulation of monocyte matrix metalloproteinase-1 production is mediated by plasmin-dependent signaling through annexin A2 and inhibited by inactive plasmin. Zhang, Y., Zhou, Z.H., Bugge, T.H., Wahl, L.M. J. Immunol. (2007) [Pubmed]
  44. The urokinase receptor (CD87) facilitates CD11b/CD18-mediated adhesion of human monocytes. Sitrin, R.G., Todd, R.F., Albrecht, E., Gyetko, M.R. J. Clin. Invest. (1996) [Pubmed]
  45. Enhanced urokinase plasminogen activation in chronic pancreatitis suggests a role in its pathogenesis. Friess, H., Cantero, D., Graber, H., Tang, W.H., Guo, X., Kashiwagi, M., Zimmermann, A., Gold, L., Korc, M., Büchler, M.W. Gastroenterology (1997) [Pubmed]
  46. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors. Kruithof, E.K., Tran-Thang, C., Gudinchet, A., Hauert, J., Nicoloso, G., Genton, C., Welti, H., Bachmann, F. Blood (1987) [Pubmed]
  47. Genistein reduces tumor necrosis factor alpha-induced plasminogen activator inhibitor-1 transcription but not urokinase expression in human endothelial cells. van Hinsbergh, V.W., Vermeer, M., Koolwijk, P., Grimbergen, J., Kooistra, T. Blood (1994) [Pubmed]
  48. Functions of the fibrinolytic system in human Ito cells and its control by basic fibroblast and platelet-derived growth factor. Fibbi, G., Pucci, M., Grappone, C., Pellegrini, G., Salzano, R., Casini, A., Milani, S., Del Rosso, M. Hepatology (1999) [Pubmed]
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