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Gene Review

Plau  -  plasminogen activator, urokinase

Mus musculus

Synonyms: U-plasminogen activator, Urokinase-type plasminogen activator, u-PA, uPA, urokinase-type plasminogen activator
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Disease relevance of Plau


Psychiatry related information on Plau


High impact information on Plau

  • All End cell lines examined expressed high levels of fibrinolytic activity resulting from increased production of urokinase-type plasminogen activator and decreased production of plasminogen activator inhibitors [8].
  • By transplanting normal human hepatocytes into SCID mice carrying a plasminogen activator transgene (Alb-uPA), we generated mice with chimeric human livers [9].
  • Homozygosity of Alb-uPA was associated with significantly higher levels of human hepatocyte engraftment, and these mice developed prolonged HCV infections with high viral titers after inoculation with infected human serum [9].
  • Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture [1].
  • Indirect evidence suggests a crucial role for the fibrinolytic system and its physiological triggers, tissue-type (t-PA) and urokinase-type (u-PA) plasminogen activator, in many proteolytic processes [10].

Chemical compound and disease context of Plau


Biological context of Plau


Anatomical context of Plau

  • Nuclear run-on analysis showed that induction of uPA mRNA by CSF-1 and phorbol myristate acetate (PMA) was at the transcriptional level in bone marrow-derived macrophages [18].
  • In contrast, uPA-/- mice had a severe regeneration defect, with decreased recruitment of blood-derived monocytes to the site of injury and with persistent myotube degeneration [17].
  • The role of plasminogen activators in skeletal muscle regeneration in vivo in wild-type, uPA-deficient, and tPA-deficient mice is investigated here [17].
  • The u-PA activity in sprouting capillaries may indicate a role in neoangiogenesis [19].
  • 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 [20].

Associations of Plau with chemical compounds

  • Peptides derived from the beta1 chain of laminin had no effect on macrophage uPA expression, whereas SIKVAV, derived from alpha1 chain, stimulated uPA expression 20-fold [21].
  • METHODS: Mice were placed into either a control group or a u-PA-inhibited group that received an in vivo u-PA inhibitor, p-aminobenzamidine [22].
  • Genistein inhibited uPA secreted by F3II cell monolayers, while inducing an increase in the proteolytic activity of B16 cells [23].
  • In vivo administration of a plasma kallikrein (pKal)-selective form of the serine protease inhibitor ecotin exacerbates the healing impairment of uPA;tPA double-deficient wounds to a degree indistinguishable from that observed in Plg-deficient mice, and completely blocks the activity of pKal, but not uPA and tPA in wound extracts [24].
  • These findings demonstrate that an additional plasminogen activator provides sufficient plasmin activity to sustain the healing process albeit at decreased speed in the absence of uPA, tPA and galardin-sensitive MMPs and suggest that pKal plays a role in plasmin generation [24].

Physical interactions of Plau

  • 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 [16].
  • These results suggest that uPA binding to integrins through the kringle domain plays an important role in both plasminogen activation and uPA-induced intracellular signaling [25].
  • Interestingly, while control and FN RGD-minus clones were able to readily bind uPA to their surface, FNwt clones exhibited impaired uPA binding [26].

Enzymatic interactions of Plau

  • Urokinase plasminogen activator (uPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin [27].

Regulatory relationships of Plau

  • These data provide insights into the clinical paradox whereby PAI-1 promotes tumor progression and warrant against the uncontrolled use of uPA/plasmin antagonists as tumor angiogenesis inhibitors [28].
  • Here, we define the molecular mechanisms of liver injury and explore whether uPA can regulate liver repair independently of plasminogen [29].
  • Preincubation of THP-1 monocytes with a monoclonal antibody directed against the alpha6 subunit of the alpha6beta1 laminin receptor blocked matrix induction of uPA without affecting the induction of MMP-9 [21].
  • Our data highlight the complexities of PA function, and suggest that approaches either to target u-PA or to enhance local t-PA activity in joints may be of therapeutic benefit in rheumatoid arthritis [30].
  • Targeted epithelial expression of a uPA-encoding transgene under the control of the keratin type-5 promoter resulted in enzyme production by the enamel epithelium, which does not normally express uPA, and altered tooth development [31].

Other interactions of Plau

  • Levels in u-PA(-)(/-) and u-PAR(-)(/-) mice were similar to those in WT mice [4].
  • Plasminogen mediates the pathological effects of urokinase-type plasminogen activator overexpression [32].
  • Additional deletion of PAI in mice with combined deficiency of t-PA and u-PA does not restore the deficient in vivo fibrinolytic capacity, but significantly reduces the thrombotic phenotype, as revealed by fewer, smaller and less calcified fibrin deposits in the liver [33].
  • In addition, uPA and MMP-2 have overlapping contributions to 4T1 migration and invasion characteristics [34].
  • In 4T1 murine mammary cancer cells, we conclude that OPN mediates metastatic behavior, in part, through upregulation of MMP-2 and uPA protein expression [34].

Analytical, diagnostic and therapeutic context of Plau


  1. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Heymans, S., Luttun, A., Nuyens, D., Theilmeier, G., Creemers, E., Moons, L., Dyspersin, G.D., Cleutjens, J.P., Shipley, M., Angellilo, A., Levi, M., Nübe, O., Baker, A., Keshet, E., Lupu, F., Herbert, J.M., Smits, J.F., Shapiro, S.D., Baes, M., Borgers, M., Collen, D., Daemen, M.J., Carmeliet, P. Nat. Med. (1999) [Pubmed]
  2. Metastatic behavior of human melanoma cell lines in nude mice correlates with urokinase-type plasminogen activator, its type-1 inhibitor, and urokinase-mediated matrix degradation. Quax, P.H., van Muijen, G.N., Weening-Verhoeff, E.J., Lund, L.R., Danø, K., Ruiter, D.J., Verheijen, J.H. J. Cell Biol. (1991) [Pubmed]
  3. Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. Gutierrez, L.S., Schulman, A., Brito-Robinson, T., Noria, F., Ploplis, V.A., Castellino, F.J. Cancer Res. (2000) [Pubmed]
  4. The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system. Swaisgood, C.M., French, E.L., Noga, C., Simon, R.H., Ploplis, V.A. Am. J. Pathol. (2000) [Pubmed]
  5. uPA deficiency exacerbates muscular dystrophy in MDX mice. Suelves, M., Vidal, B., Serrano, A.L., Tjwa, M., Roma, J., López-Alemany, R., Luttun, A., de Lagrán, M.M., Díaz-Ramos, A., Díaz, M.A., Jardí, M., Roig, M., Dierssen, M., Dewerchin, M., Carmeliet, P., Muñoz-Cánoves, P. J. Cell Biol. (2007) [Pubmed]
  6. 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]
  7. Transgenic mice overexpressing urokinase-type plasminogen activator in the brain exhibit reduced food consumption, body weight and size, and increased longevity. Miskin, R., Masos, T. J. Gerontol. A Biol. Sci. Med. Sci. (1997) [Pubmed]
  8. Increased proteolytic activity is responsible for the aberrant morphogenetic behavior of endothelial cells expressing the middle T oncogene. Montesano, R., Pepper, M.S., Möhle-Steinlein, U., Risau, W., Wagner, E.F., Orci, L. Cell (1990) [Pubmed]
  9. Hepatitis C virus replication in mice with chimeric human livers. Mercer, D.F., Schiller, D.E., Elliott, J.F., Douglas, D.N., Hao, C., Rinfret, A., Addison, W.R., Fischer, K.P., Churchill, T.A., Lakey, J.R., Tyrrell, D.L., Kneteman, N.M. Nat. Med. (2001) [Pubmed]
  10. Physiological consequences of loss of plasminogen activator gene function in mice. Carmeliet, P., Schoonjans, L., Kieckens, L., Ream, B., Degen, J., Bronson, R., De Vos, R., van den Oord, J.J., Collen, D., Mulligan, R.C. Nature (1994) [Pubmed]
  11. Preclinical studies of bismuth-213 labeled plasminogen activator inhibitor type 2 (PAI2) in a prostate cancer nude mouse xenograft model. Abbas Rizvi, S.M., Li, Y., Song, E.Y., Qu, C.F., Raja, C., Morgenstern, A., Apostolidis, C., Allen, B.J. Cancer Biol. Ther. (2006) [Pubmed]
  12. Angiotensin II increases urokinase-type plasminogen activator expression and induces aneurysm in the abdominal aorta of apolipoprotein E-deficient mice. Wang, Y.X., Martin-McNulty, B., Freay, A.D., Sukovich, D.A., Halks-Miller, M., Li, W.W., Vergona, R., Sullivan, M.E., Morser, J., Dole, W.P., Deng, G.G. Am. J. Pathol. (2001) [Pubmed]
  13. Secretion of urokinase and metalloproteinase-9 induced by staurosporine is dependent on a tyrosine kinase pathway in mammary tumor cells. Aguirre Ghiso, J.A., Farías, E.F., Alonso, D.F., Bal de Kier Joffé, E. Int. J. Cancer (1998) [Pubmed]
  14. Effects of suramin on metastatic ability, proliferation, and production of urokinase-type plasminogen activator and plasminogen activator inhibitor type 2 in human renal cell carcinoma cell line SN12C-PM6. Marutsuka, K., Hasui, Y., Asada, Y., Naito, S., Osada, Y., Sumiyoshi, A. Clin. Exp. Metastasis (1995) [Pubmed]
  15. An interspecific backcross linkage map of the proximal half of mouse chromosome 14. Ceci, J.D., Kingsley, D.M., Silan, C.M., Copeland, N.G., Jenkins, N.A. Genomics (1990) [Pubmed]
  16. Receptor-independent role of urokinase-type plasminogen activator in pericellular plasmin and matrix metalloproteinase proteolysis during vascular wound healing in mice. Carmeliet, P., Moons, L., Dewerchin, M., Rosenberg, S., Herbert, J.M., Lupu, F., Collen, D. J. Cell Biol. (1998) [Pubmed]
  17. Urokinase-dependent plasminogen activation is required for efficient skeletal muscle regeneration in vivo. Lluís, F., Roma, J., Suelves, M., Parra, M., Aniorte, G., Gallardo, E., Illa, I., Rodríguez, L., Hughes, S.M., Carmeliet, P., Roig, M., Muñoz-Cánoves, P. Blood (2001) [Pubmed]
  18. Regulation of urokinase-type plasminogen activator gene transcription by macrophage colony-stimulating factor. Stacey, K.J., Fowles, L.F., Colman, M.S., Ostrowski, M.C., Hume, D.A. Mol. Cell. Biol. (1995) [Pubmed]
  19. Expression of plasminogen activators and plasminogen activator inhibitors in cutaneous melanomas of transgenic melanoma-susceptible mice. de Vries, T.J., Kitson, J.L., Silvers, W.K., Mintz, B. Cancer Res. (1995) [Pubmed]
  20. Proteinase expression in early mouse embryos is regulated by leukaemia inhibitory factor and epidermal growth factor. Harvey, M.B., Leco, K.J., Arcellana-Panlilio, M.Y., Zhang, X., Edwards, D.R., Schultz, G.A. Development (1995) [Pubmed]
  21. Role of laminin in matrix induction of macrophage urokinase-type plasminogen activator and 92-kDa metalloproteinase expression. Khan, K.M., Falcone, D.J. J. Biol. Chem. (1997) [Pubmed]
  22. Inhibition of urokinase-type plasminogen activator delays expression of c-jun, activated transforming growth factor beta 1, and matrix metalloproteinase 2 during post-hepatectomy liver regeneration in mice. Nomura, K., Miyagawa, S., Ayukawa, K., Soeda, J., Taniguchi, S., Kawasaki, S. J. Hepatol. (2002) [Pubmed]
  23. Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer. Farina, H.G., Pomies, M., Alonso, D.F., Gomez, D.E. Oncol. Rep. (2006) [Pubmed]
  24. Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice. Lund, L.R., Green, K.A., Stoop, A.A., Ploug, M., Almholt, K., Lilla, J., Nielsen, B.S., Christensen, I.J., Craik, C.S., Werb, Z., Danø, K., Rømer, J. EMBO J. (2006) [Pubmed]
  25. Direct interaction of the kringle domain of urokinase-type plasminogen activator (uPA) and integrin alpha v beta 3 induces signal transduction and enhances plasminogen activation. Tarui, T., Akakura, N., Majumdar, M., Andronicos, N., Takagi, J., Mazar, A.P., Bdeir, K., Kuo, A., Yarovoi, S.V., Cines, D.B., Takada, Y. Thromb. Haemost. (2006) [Pubmed]
  26. Involvement of fibronectin in the regulation of urokinase production and binding in murine mammary tumor cells. Urtreger, A.J., Aguirre Ghiso, J.A., Werbajh, S.E., Puricelli, L.I., Muro, A.F., Bal de Kier Joff, E. Int. J. Cancer (1999) [Pubmed]
  27. Urokinase-type plasminogen activator potentiates lipopolysaccharide-induced neutrophil activation. Abraham, E., Gyetko, M.R., Kuhn, K., Arcaroli, J., Strassheim, D., Park, J.S., Shetty, S., Idell, S. J. Immunol. (2003) [Pubmed]
  28. The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. Bajou, K., Masson, V., Gerard, R.D., Schmitt, P.M., Albert, V., Praus, M., Lund, L.R., Frandsen, T.L., Brunner, N., Dano, K., Fusenig, N.E., Weidle, U., Carmeliet, G., Loskutoff, D., Collen, D., Carmeliet, P., Foidart, J.M., Noël, A. J. Cell Biol. (2001) [Pubmed]
  29. Plasminogen directs the pleiotropic effects of uPA in liver injury and repair. Currier, A.R., Sabla, G., Locaputo, S., Melin-Aldana, H., Degen, J.L., Bezerra, J.A. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) [Pubmed]
  30. Differing roles for urokinase and tissue-type plasminogen activator in collagen-induced arthritis. Cook, A.D., Braine, E.L., Campbell, I.K., Hamilton, J.A. Am. J. Pathol. (2002) [Pubmed]
  31. Extracellular proteolysis alters tooth development in transgenic mice expressing urokinase-type plasminogen activator in the enamel organ. Zhou, H.M., Nichols, A., Wohlwend, A., Bolon, I., Vassalli, J.D. Development (1999) [Pubmed]
  32. Plasminogen mediates the pathological effects of urokinase-type plasminogen activator overexpression. Bolon, I., Zhou, H.M., Charron, Y., Wohlwend, A., Vassalli, J.D. Am. J. Pathol. (2004) [Pubmed]
  33. Biological effects of combined inactivation of plasminogen activator and plasminogen activator inhibitor-1 gene function in mice. Lijnen, H.R., Moons, L., Beelen, V., Carmelie, P., Collen, D. Thromb. Haemost. (1995) [Pubmed]
  34. Integrin-linked kinase regulates osteopontin-dependent MMP-2 and uPA expression to convey metastatic function in murine mammary epithelial cancer cells. Mi, Z., Guo, H., Wai, P.Y., Gao, C., Kuo, P.C. Carcinogenesis (2006) [Pubmed]
  35. Urokinase and tissue-type plasminogen activator are required for the mitogenic and chemotactic effects of bovine fibroblast growth factor and platelet-derived growth factor-BB for vascular smooth muscle cells. Herbert, J.M., Lamarche, I., Carmeliet, P. J. Biol. Chem. (1997) [Pubmed]
  36. Characterization of the functional epitope on the urokinase receptor. Complete alanine scanning mutagenesis supplemented by chemical cross-linking. Gårdsvoll, H., Gilquin, B., Le Du, M.H., Ménèz, A., Jørgensen, T.J., Ploug, M. J. Biol. Chem. (2006) [Pubmed]
  37. Effect of steroids on CSF matrix metalloproteinases in multiple sclerosis: relation to blood-brain barrier injury. Rosenberg, G.A., Dencoff, J.E., Correa, N., Reiners, M., Ford, C.C. Neurology (1996) [Pubmed]
  38. Expression and function of the urokinase type plasminogen activator during mouse hemochorial placental development. Teesalu, T., Blasi, F., Talarico, D. Dev. Dyn. (1998) [Pubmed]
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