Cancer and Metastasis Reviews

, Volume 22, Issue 2–3, pp 205–222

The urokinase plasminogen activator system in cancer: Recent advances and implication for prognosis and therapy



Cancer dissemination and metastasis is synonymous with invasive cell migration; a process in which the extracellular matrix (ECM) plays the dual role of the substratum on which the cells move as well as the physical obstacle that the cells have to surpass. To degrade the physical obstacle, which the ECM poses in the direction of migration, cells use proteolytic enzymes capable of degrading the ECM components. A major protease system responsible for ECM degradation is the plasminogen activation system, which generates the potent serine protease plasmin. The subject of this review, the urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plays an impressive range of distinct, but overlapping functions in the process of cancer invasion and metastasis: Firstly, uPA/uPAR promotes extracellular proteolysis by regulating plasminogen activation. Secondly, uPA/uPAR regulates cell/ECM interactions as an adhesion receptor for vitronectin (Vn) and through its capacity to modulate integrin function. Thirdly, uPA/uPAR regulates cell migration as a signal transduction molecule and by its intrinsic chemotactic activity. This review is focused on recent insight into the cancer related biology of the uPA/uPAR system as well as its implications for clinical cancer diagnosis, prognosis and therapy.

uPA uPAR vitronectin integrins cell adhesion cell migration tumor invasion prognostic markers toxins 


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  1. 1.
    PöllÄnen J, Stephens R, Salonen EM, Vaheri A: Proteolytic mechanisms operating at the surface of invasive cells. Adv Exp Med Biol 233: 187–199, 1988Google Scholar
  2. 2.
    PöllÄnen J, Vaheri A, Tapiovaara H, Riley E, Bertram K, Woodrow G, Stephens RW: Prourokinase activation on the surface of human rhabdomyosarcoma cells: Localization and inactivation of newly formed urokinase-type plasminogen activator by recombinant class 2 plasminogen activator inhibitor. Proc Natl Acad Sci USA 87: 2230–2234, 1990Google Scholar
  3. 3.
    Bajpai A, Baker JB: Cryptic urokinase binding sites on human foreskin fibroblasts. Biochem Biophys Res Commun 133: 475–482, 1985Google Scholar
  4. 4.
    Vassalli JD, Baccino D, Belin D: A cellular binding site for the Mr 55,000 form of the human plasminogen activator, urokinase. J Cell Bio l 100: 86–92, 1985Google Scholar
  5. 5.
    Stoppelli MP, Corti A, Soffientini A, Cassani G, Blasi F, Associan RK: Differentiation-enhanced binding of the aminoterminal fragment of human urokinase plasminogen activator to a specific receptor on U937 monocytes. PNAS 82: 4939–4943, 1985Google Scholar
  6. 6.
    Roldan AL, Cubellis MV, Masucci MT, Behrendt N, Lund LR, Danø K, Appella E, Blasi F: Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin dependent proteolysis [published erratum appears in EMBO J 9(5):1674, May 1990]. EMBO J 9: 467–474, 1990Google Scholar
  7. 7.
    Ploug M, Rønne E, Behrendt N, Jensen AL, Blasi F Danø K: Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol. J Biol Chem 266: 1926–1933, 1991Google Scholar
  8. 8.
    Møller LB, Ploug M, Blasi F: Structural requirements for glycosyl-phosphatidylinositol-anchor attachment in the cellular receptor for urokinase plasminogen activator. Eur J Biochem 208: 493–500, 1992Google Scholar
  9. 9.
    Behrendt N, Ploug M, Patthy L, Houen G, Blasi F, Danø K: The ligand-binding domain of the cell surface receptor for urokinase-type plasminogen activator. J Biol Chem 266: 7842–7847, 1991Google Scholar
  10. 10.
    Ploug M, Kjalke M, Rønne E, Weidle U, Høyer-Hansen G, Danø K: Localization of the disulfide bonds in the NH2-terminal domain of the cellular receptor for human urokinase-type plasminogen activator. A domain structure belonging to a novel superfamily of glycolipid-anchored membrane proteins. J Biol Chem 268: 17539–17546, 1993Google Scholar
  11. 11.
    Wun TC, Reich E: An inhibitor of plasminogen activation fromhum an placenta. Purification and characterization. J Biol Chem 262: 3646–3653, 1987Google Scholar
  12. 12.
    Wiman B, Lindahl T, Almqvist A: Evidence for a discrete binding protein of plasminogen activator inhibitor in plasma. Thromb Haemost 59: 392–395, 1988Google Scholar
  13. 13.
    PöllÄnen J, Saksela O, Salonen EM, Andreasen P, Nielsen L, Danø K, Vaheri A: Distinct localizations of urokinasetype plasminogen activator and its type 1 inhibitor under cultured human fibroblasts and sarcoma cells. J Cell Biol 104: 1085–1096, 1987Google Scholar
  14. 14.
    Declerck PJ, De Mol M, Alessi MC, Baudner S, Paques EP, Preissner KT, Müller Berghaus G, Collen D: Purification and characterization of a plasminogen activator inhibitor 1 binding protein from human plasma. Identification as a multimeric form of S protein (vitronectin). J Biol Chem 263: 15454–15461, 1988Google Scholar
  15. 15.
    Salonen EM, Vaheri A, PöllÄnen J, Stephens R, Andreasen P, Mayer M, Danø K, Gailit J, Ruoslahti E: Interaction of plasminogen activator inhibitor (PAI-1) with vitronectin. J Biol Chem 264: 6339–6343, 1989Google Scholar
  16. 16.
    Bajou K, Lewalle JM, Martinez CR, Soria C, Lu H, Noel A, Foidart JM: Human breast adenocarcinoma cell lines promote angiogenesis by providing cells with uPA-PAI-1 and by enhancing their expression. Int J Cancer 100: 501–506, 2002Google Scholar
  17. 17.
    Pedersen N, Schmitt M, Rønne E, Nicoletti MI, Høyer-Hansen G, Conese M, Giavazzi R, Danø K, Kuhn W, JÄnicke F, Blasi F: A ligand-free, soluble urokinase receptor is present in the ascitic fluid frompatients with ovarian cancer. J Clin Invest 92: 2160–2167, 1993Google Scholar
  18. 18.
    Sier CFM, Stephens RW, Bizik J, Mariani A, Bassan M, Pedersen N, Frigerio L, Ferrari A, Danø K, Brünner N, Blasi F: The level of urokinase-type plasminogen activator receptor is increased in serumof ovarian cancer patients. Cancer Res 58: 1843–1849, 1998Google Scholar
  19. 19.
    Metz CN, Brunner G, Choi Muira NH, Nguyen H, Gabrilove J, Caras IW, Altszuler N, Rifkin DB, Wilson EL, Davitz MA: Release of GPI-anchored membrane proteins by a cell-associated GPI-specific phospholipase D. EMBO J 13: 1741–1751, 1994Google Scholar
  20. 20.
    Wilhelm OG, Wilhelm S, Escott GM, Lutz V, Magdolen V, Schmitt M, Rifkin DB, Wilson EL, Graeff H, Brunner G: Cellular glycosylphosphatidylinositol-specific phospholipase D regulates urokinase receptor shedding and cell surface expression. J Cell Physiol 180: 225–235, 1999Google Scholar
  21. 21.
    Rønne E, Behrendt N, Ploug M, Nielsen HJ, Wöllisch E, Weidle U, Danø K, Høyer Hansen G: Quantitation of the receptor for urokinase plasminogen activator by enzymelinked immunosorbent assay. J Immunol Methods 167: 91–101, 1994Google Scholar
  22. 22.
    Wei Y, Waltz DA, Rao N, Drummond RJ, Rosenberg S, Chapman HA: Identification of the urokinase receptor as an adhesion receptor for vitronectin. J Biol Chem 69: 32380–32388, 1994Google Scholar
  23. 23.
    Lau HK, Kim M: Soluble urokinase receptor from fibrosarcoma HT-1080 cells. Blood Coagul Fibrinolysis 5: 473–478, 1994Google Scholar
  24. 24.
    Chavakis T, Kanse SM, Yutzy B, Lijnen HR, Preissner KT: Vitronectin concentrates proteolytic activity on the cell surface and extracellular matrix by trapping soluble urokinase receptor-urokinase complexes. Blood 91: 2305–2312, 1998Google Scholar
  25. 25.
    Sidenius N, Sier CFM, Blasi F: Shedding and cleavage of the urokinase receptor (uPAR): Identification and characterization of uPAR fragments in vitro and in vivo. FEBS Lett 475: 52–56, 2000Google Scholar
  26. 26.
    Holst-Hansen C, Hamers MJ, Johannessen BE, Brünner N, Stephens RW: Soluble urokinase receptor released from human carcinoma cells: A plasma parameter for xenograft tumor studies. Br J Cancer 81: 203–211, 1999Google Scholar
  27. 27.
    Wahlberg K, Høyer-Hansen G, CasslÈn B: Soluble receptor for urokinase plasminogen activator in both full-length and a cleaved formis present in high concentration in cystic fluid fromovarian cancer. Cancer Res 58: 3294–3298, 1998Google Scholar
  28. 28.
    Sier CF, Sidenius N, Mariani A, Aletti G, Agape V, Ferrari A, Casetta G, Stephens RW, Brünner N, Blasi F: Presence of urokinase-type plasminogen activator receptor in urine of cancer patients and its possible clinical relevance. Lab Invest 79: 717–722, 1999Google Scholar
  29. 29.
    Stephens RW, Pedersen AN, Nielsen HJ, Hamers MJ, Høyer Hansen G, Rønne E, Dybkjær E, Danø K, Brünner N: ELISA determination of soluble urokinase receptor in blood fromhealthy donors and cancer patients. Clin Chem 43: 1868–1876, 1997Google Scholar
  30. 30.
    Mustjoki S, Sidenius N, Sier CF, Blasi F, Elonen E, Alitalo R, Vaheri A: Soluble urokinase receptor levels correlate with number of circulating tumor cells in acute myeloid leukemia and decrease rapidly during chemotherapy. Cancer Res 60: 7126–7132, 2000Google Scholar
  31. 31.
    Garcia-Monco J, Coleman J, Benach J: Soluble urokinase receptor (uPAR, CD 87) is present in serumand cerebrospinal fluid in patients with neurologic diseases. J Neuroimmunol 129: 216, 2002Google Scholar
  32. 32.
    Ploug M, Ellis V, Danø K: Ligand interaction between urokinase-type plasminogen activator and its receptor probed with 8-anilino-1-naphthalenesulfonate. Evidence for a hydrophobic binding site exposed only on the intact receptor. Biochemistry 33: 8991–8997, 1994Google Scholar
  33. 33.
    Høyer-Hansen G, Behrendt N, Ploug M, Danø K, Preissner KT: The intact urokinase receptor is required for efficient vitronectin binding: Receptor cleavage prevents ligand interaction. FEBS Lett 420: 79–85, 1997Google Scholar
  34. 34.
    Koolwijk P, Sidenius N, Peters E, Sier CF, Hanemaaijer R, Blasi F, van Hinsbergh VW: Proteolysis of the urokinase-type plasminogen activator receptor by metalloproteinase-12: Implication for angiogenesis in fibrin matrices. Blood 97: 3123–3131, 2001Google Scholar
  35. 35.
    Andolfo A, English WR, Resnati M, Murphy G, Blasi F, Sidenius N: Metalloproteases cleave the urokinase-type plasminogen activator receptor in the D1-D2 linker region and expose epitopes not present in the intact soluble receptor. Thromb Haemost 88: 298–306, 2002Google Scholar
  36. 36.
    Høyer-Hansen G, Rønne E, Solberg H, Behrendt N, Ploug M, Lund LR, Ellis V, Danø K: Urokinase plasminogen activator cleaves its cell surface receptor releasing the ligand-binding domain. J Biol Chem 267: 18224–18229, 1992Google Scholar
  37. 37.
    Høyer-Hansen G, Ploug M, Behrendt N, Rønne E, Danø K: Cell-surface acceleration of urokinase-catalyzed receptor cleavage. Eur J Biochem 243: 21–26, 1997Google Scholar
  38. 38.
    Høyer-Hansen G, Pessara U, Holm A, Pass J, Weidle U, Danø K, Behrendt N: Urokinase-catalyzed cleavage of the urokinase receptor requires an intact glycolipid anchor. Biochem J 358: 673–679, 2001Google Scholar
  39. 39.
    Solberg H, Rømer J, Brünner N, Holm A, Sidenius N, Danø K, Høyer-Hansen G: A cleaved formof the receptor for urokinase-type plasminogen activator in invasive transplanted human and murine tumors. Int J Cancer 58: 877–881, 1994Google Scholar
  40. 40.
    Ragno P, Montuori N, Covelli B, Høyer-Hansen G, Rossi G: Differential expression of a truncated formof the urokinase-type plasminogen-activator receptor in normal and tumor thyroid cells. Cancer Res 58: 1315–1319, 1998Google Scholar
  41. 41.
    Mustjoki S, Sidenius N, Vaheri A: Enhanced release of soluble urokinase receptor by endothelial cells in contact with peripheral blood cells. FEBS Lett 486: 237–242, 2000Google Scholar
  42. 42.
    Appella E, Robinson EA, Ullrich SJ, Stoppelli MP, Corti A, Cassani G, Blasi F: The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. J Biol Chem 262: 4437–4440, 1987Google Scholar
  43. 43.
    Muehlenweg B, Sperl S, Magdolen V, Schmitt M, Harbeck N: Interference with the urokinase plasminogen activator system: A promising therapy concept for solid tumors. Expert Opin Biol Ther 1: 683–691,2001Google Scholar
  44. 44.
    Ploug M: Identification of specific sites involved in ligand binding by photoaffinity labeling of the receptor for the urokinase-type plasminogen activator. Residues located at equivalent positions in uPAR domains I and III participate in the assembly of a composite ligand-binding site. Biochemistry 37: 16494–16505, 1998Google Scholar
  45. 45.
    Preissner KT: The role of vitronectin as multifunctional regulator in the hemostatic and immune systems. Blut 59: 419–431, 1989Google Scholar
  46. 46.
    Waltz DA, Chapman HA: Reversible cellular adhesion to vitronectin linked to urokinase receptor occupancy. J Biol Chem 269: 14746–14750, 1994Google Scholar
  47. 47.
    Kanse SM, Kost C, Wilhelm OG, Andreasen PA, Preissner KT: The urokinase receptor is a major The urokinase plasminogen activator system in cancer 217 vitronectin-binding protein on endothelial cells. Exp Cell Res 224: 344–353, 1996Google Scholar
  48. 48.
    Sidenius N, Blasi F: Domain 1 of the urokinase receptor (uPAR) is required for uPAR-mediated cell binding to vitronectin. FEBS Lett 470: 40–46, 2000Google Scholar
  49. 49.
    Deng G, Curriden SA, Wang S, Rosenberg S, Loskutoff DJ: Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release? J Cell Biol 134: 1563–1571, 1996Google Scholar
  50. 50.
    Okumura Y, Kamikubo Y, Curriden SA, Wang J, Kiwada T, Futaki S, Kitagawa K, Loskutoff DJ: Kinetic analysis of the interaction between vitronectin and the urokinase receptor. J Biol Chem 31: 31, 2001Google Scholar
  51. 51.
    Sidenius N, Andolfo A, Fesce R, Blasi F: Urokinase regulates vitronectin binding by controlling urokinase receptor oligomerization. J Biol Chem 277: 27982–27990, 2002Google Scholar
  52. 52.
    Montuori N, Carriero MV, Salzano S, Rossi G, Ragno P: The cleavage of the urokinase receptor regulates its multiple functions. J Biol Chem 23: 23, 2002Google Scholar
  53. 53.
    Liu D, Ghiso JA, Estrada Y, Ossowski L: EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell 1: 445–457, 2002Google Scholar
  54. 54.
    Resnati M, Guttinger M, Valcamonica S, Sidenius N, Blasi F, Fazioli F: Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect. EMBO J 15: 1572–1582, 1996Google Scholar
  55. 55.
    Fazioli F, Resnati M, Sidenius N, Higashimoto Y, Appella E, Blasi F: A urokinase-sensitive region of the human urokinase receptor is responsible for its chemotactic activity. EMBO J 16: 7279–7286, 1997Google Scholar
  56. 56.
    Colman RW, Pixley RA, Najamunnisa S, Yan W, Wang J, Mazar A, McCrae KR: Binding of high molecular weight kininogen to human endothelial cells is mediated via a site within domains 2 and 3 of the urokinase receptor. J Clin Invest 100: 1481–1487, 1997Google Scholar
  57. 57.
    Higazi AA, Upson RH, Cohen RL, Manuppello J, Bognacki J, Henkin J, McCrae KR, Kounnas MZ, Strickland DK, Preissner KT, Lawler, Cines DB: Interaction of single-chain urokinase with its receptor induces the appearance and disappearance of binding epitopes within the resultant complex for other cell surface proteins. Blood 88: 542–551, 1996Google Scholar
  58. 58.
    Czekay RP, Kuemmel TA, Orlando RA, Farquhar MG: 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. Mol Biol Cell 12: 1467–1479, 2001Google Scholar
  59. 59.
    Behrendt N, Jensen ON, Engelholm LH, Mortz E, Mann M, Dano K: A urokinase receptor-associated protein with specific collagen binding properties. J Biol Chem 275: 1993–2002, 2000Google Scholar
  60. 60.
    Nykjaer A, Christensen EI, Vorum H, Hager H, Petersen CM, Ráigaard H, Min HY, Vilhardt F, Møller LB, Kornfeld S, Gliemann J: Mannose 6-phosphate/insulinlike growth factor-II receptor targets the urokinase receptor to lysosomes via a novel binding interaction. J Cell Biol 141: 815–828, 1998Google Scholar
  61. 61.
    Chapman HA, Wei Y: Protease crosstalk with integrins: The urokinase receptor paradigm. Thromb Haemost 86: 124–129, 2001Google Scholar
  62. 62.
    Ossowski L, Aguirre-Ghiso JA: Urokinase receptor and integrin partnership: Coordination of signaling for cell adhesion, migration and growth. Curr Opin Cell Biol 12: 613–620, 2000Google Scholar
  63. 63.
    Andreasen PA, Kjøller L, Christensen L, Duffy MJ: The urokinase-type plasminogen activator system in cancer metastasis: A review. Int J Cancer 72: 1–22, 1997Google Scholar
  64. 64.
    Danø K, Rømer J, Nielsen BS, Bjørn S, Pyke C, Rygaard J, Lund LR: Cancer invasion and tissue remodeling-cooperation of protease systems and cell types. APMIS 107: 120–127, 1999Google Scholar
  65. 65.
    Johnsen M, Lund LR, Rømer J, Almholt K, Danø K: Cancer invasion and tissue remodeling: Common themes in proteolytic matrix degradation. Curr Opin Cell Biol 10: 667–671, 1998Google Scholar
  66. 66.
    Plesner T, Ralfkiaer E, Wittrup M, Johnsen H, Pyke C, Pedersen TL, Hansen NE, Danø K: Expression of the receptor for urokinase-type plasminogen activator in normal and neoplastic blood cells and hematopoietic tissue. AmJ Clin Pathol 102: 835–841, 1994Google Scholar
  67. 67.
    Lanza F, Castoldi GL, Castagnari B, Todd RF, 3rd, Moretti S, Spisani S, Latorraca A, Focarile E, Roberti MG, Traniello S: Expression and functional role of urokinase-type plasminogen activator receptor in normal and acute leukaemic cells. Br J Haematol 103: 110–123, 1998Google Scholar
  68. 68.
    Mustjoki S, Alitalo R, Stephens RW, Vaheri A: Blast cell surface and plasma soluble urokinase receptor in acute leukemia patients: Relationship to classification and response to therapy. Thromb Haemost 81: 705–710, 1999Google Scholar
  69. 69.
    Carriero MV, Del Vecchio S, Franco P, Potena MI, Chiaradonna F, Botti G, Stoppelli MP, Salvatore M: Vitronectin binding to urokinase receptor in human breast cancer. Clin Cancer Res 3: 1299–1308, 1997Google Scholar
  70. 70.
    Morita S, Sato A, Hayakawa H, Ihara H, Urano T, Takada Y, Takada A: Cancer cells overexpress mRNA of urokinase-type plasminogen activator, its receptor and inhibitors in human non-small-cell lung cancer tissue: Analysis by Northern blotting and in situ hybridization. Int J Cancer 78: 286–292, 1998Google Scholar
  71. 71.
    Hudson MA, McReynolds LM: Urokinase and the urokinase receptor: Association with in vitro invasiveness of human bladder cancer cell lines [see comments]. J Natl Cancer Inst 89: 709–717, 1997Google Scholar
  72. 72.
    Pyke C, Kristensen P, Ralfkiaer E, Grøndahl-Hansen J, Eriksen J, Blasi F, Danø K: Urokinase-type plasminogen activator is expressed in stromal cells and its receptor in cancer cells at invasive foci in human colon adenocarcinomas. Am J Pathol 138: 1059–1067, 1991Google Scholar
  73. 73.
    De Petro G, Tavian D, Copeta A, Portolani N, Giulini SM, Barlati S: Expression of urokinase-type plasminogen activator (u-PA), u-PA receptor, and tissue-type PA messenger RNAs in human hepatocellular carcinoma. Cancer Res 58: 2234–2239, 1998Google Scholar
  74. 74.
    Shetty S, Idell S: A urokinase receptor mRNA binding protein-mRNA interaction regulates receptor expression and function in human pleural mesothelioma cells. Arch BiochemBiophys 356: 265–279, 1998Google Scholar
  75. 75.
    Taniguchi T, Kakkar AK, Tuddenham EG, Williamson RC, Lemoine NR: Enhanced expression of urokinase receptor induced through the tissue factor-factor VIIa pathway in human pancreatic cancer. Cancer Res 58: 4461–4467, 1998Google Scholar
  76. 76.
    Yamamoto M, Sawaya R, Mohanam S, Rao VH, Bruner JM, Nicolson GL, Rao JS: Expression and localization of urokinase-type plasminogen activator receptor in human gliomas. Cancer Res 54: 5016–5020, 1994Google Scholar
  77. 77.
    Yamamoto M, Sawaya R, Mohanam S, Rao VH, Bruner JM, Nicolson GL, Ohshima K, Rao JS: Activities, localizations, and roles of serine proteases and their inhibitors in human brain tumor progression. J Neurooncol 22: 139–151, 1994Google Scholar
  78. 78.
    Ellis V, Scully MF, Kakkar VV: Plasminogen activation initiated by single-chain urokinase-type plasminogen activator. Potentiation by U937 monocytes. J Biol Chem 264: 2185–2188, 1989Google Scholar
  79. 79.
    Ellis V, Behrendt N, Danø K: Plasminogen activation by receptor-bound urokinase. A kinetic study with both cellassociated and isolated receptor. J Biol Chem 266: 12752–12758, 1991Google Scholar
  80. 80.
    Rønne E, Behrendt N, Ellis V, Ploug M, Danø K, Høyer-Hansen G: Cell-induced potentiation of the plasminogen activation systemis abolished by a monoclonal antibody that recognizes the NH2-terminal domain of the urokinase receptor. FEBS Lett 288: 233–236, 1991Google Scholar
  81. 81.
    Stephens RW, Tapiovaara H, Reisberg T, Bizik J, Vaheri A: Alpha 2-macroglobulin restricts plasminogen activation to the surface of RC2A leukemia cells. Cell Regul 2: 1057–1065, 1991Google Scholar
  82. 82.
    Cubellis MV, Andreasen P, Ragno P, Mayer M, Danø K, Blasi F: Accessibility of receptor-bound urokinase to type-1 plasminogen activator inhibitor. Proc Natl Acad Sci USA 86: 4828–4832, 1989Google Scholar
  83. 83.
    Stephens RW, PöllÄnen J, Tapiovaara H, Leung KC, Sim PS, Salonen EM, Rønne E, Behrendt N, Danø K, Vaheri A: Activation of pro-urokinase and plasminogen on human sarcoma cells: A proteolytic system with surfacebound reactants. J Cell Biol 108: 1987–1995, 1989Google Scholar
  84. 84.
    Ellis V, Wun TC, Behrendt N, Rønne E, Danø K: Inhibition of receptor-bound urokinase by plasminogenactivator inhibitors. J Biol Chem 265: 9904–9908, 1990Google Scholar
  85. 85.
    Estreicher A, MÜhlhauser J, Carpentier JL, Orci L, Vassalli JD: The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes. J Cell Biol 111: 783–792, 1990Google Scholar
  86. 86.
    Rømer J, Lund LR, Eriksen J, Pyke C, Kristensen P, Danø K: The receptor for urokinase-type plasminogen activator is expressed by keratinocytes at the leading edge during re-epithelialization of mouse skin wounds. J Invest Dermatol 102: 519–522, 1994Google Scholar
  87. 87.
    Conforti G, Dominguez-Jimenez C, Rønne E, Høyer-Hansen G, Dejana E: Cell-surface plasminogen activation causes a retraction of in vitro cultured human umbilical vein endothelial cell monolayer. Blood 83: 994–1005, 1994Google Scholar
  88. 88.
    Conese M, Blasi F: The urokinase/urokinase-receptor systemand cancer invasion. Baillieres Clin Haematol 8: 365–389, 1995Google Scholar
  89. 89.
    Xue W, Mizukami I, Todd RFr, Petty HR: Urokinasetype plasminogen activator receptors associate with beta1 and beta3 integrins of fibrosarcoma cells: Dependence on extracellular matrix components. Cancer Res 57: 1682–1689, 1997Google Scholar
  90. 90.
    Mizukami IF, Todd RFr: A soluble form of the urokinase plasminogen activator receptor (suPAR) can bind to hematopoietic cells. J Leukoc Biol 64: 203–213, 1998Google Scholar
  91. 91.
    Stephens RW, Nielsen HJ, Christensen IJ, Thorlacius Ussing O, Sørensen S, Danø K, Brünner N: Plasma urokinase receptor levels in patients with colorectal cancer: Relationship to prognosis. J Natl Cancer Inst 91: 869–874, 1999Google Scholar
  92. 92.
    Higazi AA, Bdeir K, Hiss E, Arad S, Kuo A, Barghouti I, Cines DB: Lysis of plasma clots by urokinase-soluble urokinase receptor complexes. Blood 92: 2075–2083, 1998Google Scholar
  93. 93.
    Cubellis MV, Wun TC, Blasi F: Receptor-mediated internalization and degradation of urokinase is caused by its specific inhibitor PAI-1. EMBO J 9: 1079–1085, 1990Google Scholar
  94. 94.
    Jensen PH, Christensen EI, Ebbesen P, Gliemann J, Andreasen PA: Lysosomal degradation of receptor-bound urokinase-type plasminogen activator is enhanced by its inhibitors in human trophoblastic choriocarcinoma cells. Cell Regul 1: 1043–1056, 1990Google Scholar
  95. 95.
    Herz J, Clouthier DE, Hammer RE: LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation [published erratumappears in Cell 73(3): 428 May 7 1993]. Cell 71: 411–421, 1992Google Scholar
  96. 96.
    Nykjaer A, Petersen CM, Møller B, Jensen PH, Moestrup SK, Holtet TL, Etzerodt M, Thøgersen HC, Munch M, Andreasen PA, et al: Purified alpha 2-macroglobulin receptor/LDL receptor-related protein binds urokinaseplasminogen activator inhibitor type-1 complex. Evidence that the alpha 2-macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes. J Biol Chem 267: 14543–14546, 1992Google Scholar
  97. 97.
    Moestrup SK, Holtet TL, Etzerodt M, Thøgersen HC, Nykjaer A, Andreasen PA, Rasmussen HH, Sottrup Jensen L, Gliemann J: Alpha 2-macroglobulin-proteinase complexes, plasminogen activator inhibitor type-1-plasminogen activator complexes, and receptor-associated protein bind to a region of the alpha 2-macroglobulin receptor containing a cluster of eight complement-type repeats. J Biol Chem 268: 13691–13696, 1993Google Scholar
  98. 98.
    Heegaard CW, Simonsen AC, Oka K, Kjøller L, Christensen A, Madsen B, Ellgaard L, Chan L, Andreasen PA: Very low density lipoprotein receptor binds and mediates endocytosis of urokinase-type plasminogen activator-type-1 plasminogen activator inhibitor complex. J Biol Chem 270: 20855–20861, 1995Google Scholar
  99. 99.
    Nykjaer A, Conese M, Christensen EI, Olson D, Cremona O, Gliemann J, Blasi F: Recycling of the urokinase receptor upon internalization of the uPA: Serpin complexes. EMBO J 16: 2610–2620, 1997Google Scholar
  100. 100.
    Chang AW, Kuo A, Barnathan ES, Okada SS: Urokinase receptor-dependent upregulation of smooth muscle cell The urokinase plasminogen activator system in cancer 219 adhesion to vitronectin by urokinase. Arterioscler Thromb Vasc Biol 18: 1855–1860, 1998Google Scholar
  101. 101.
    Kjøller L, Hall A: Rac mediates cytoskeletal rearrangements and increased cell motility induced by urokinasetype Plasminogen activator receptor binding to vitronectin. J Cell Biol 152: 1145–1157, 2001Google Scholar
  102. 102.
    Wei Y, Lukashev M, Simon DI, Bodary SC, Rosenberg S, Doyle MV, Chapman HA: Regulation of integrin function by the urokinase receptor. Science 273: 1551–1555, 1996Google Scholar
  103. 103.
    Degryse B, Orlando S, Resnati M, Rabbani SA, Blasi F: Urokinase/urokinase receptor and vitronectin/alpha(v)-beta(3) integrin induce chemotaxis and cytoskeleton reorganization through different signaling pathways. Oncogene 20: 2032–2043, 2001Google Scholar
  104. 104.
    Kjøller L: The urokinase plasminogen activator receptor in the regulation of the actin cytoskeleton and cell motility. Biol Chem 383: 5–19, 2002Google Scholar
  105. 105.
    Blasi F: uPA, uPAR, PAI-1: key intersection of proteolytic, adhesive and chemotactic highways? Immunol Today 18: 415–417, 1997Google Scholar
  106. 106.
    Knudsen BS, Nachman RL: Matrix plasminogen activator inhibitor. Modulation of the extracellular proteolytic environment. J Biol Chem 263: 9476–9481, 1988Google Scholar
  107. 107.
    Seiffert D, Loskutoff DJ: Evidence that type 1 plasminogen activator inhibitor binds to the somatomedin B domain of vitronectin. J Biol Chem 266: 2824–2830, 1991Google Scholar
  108. 108.
    Stefansson S, Lawrence DA: The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta3 binding to vitronectin [see comments]. Nature 383: 441–443, 1996Google Scholar
  109. 109.
    Kjøller L, Kanse SM, Kirkegaard T, Rodenburg KW, Rønne E, Goodman SL, Preissner KT, Ossowski L, Andreasen PA: Plasminogen activator inhibitor-1 represses integrin-and vitronectin-mediated cell migration independently of its function as an inhibitor of plasminogen activation. Exp Cell Res 232: 420–429, 1997Google Scholar
  110. 110.
    Li S, Couet J, Lisanti MP: Src tyrosine kinases, Galpha subunits, and H-Ras share a common membrane anchored scaffolding protein, caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases. J Biol Chem 271: 29182–29190, 1996Google Scholar
  111. 111.
    Wary KK, Mariotti A, Zurzolo C, Giancotti FG: A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth. Cell 94: 625–634, 1998Google Scholar
  112. 112.
    Stahl A, Mueller BM: The urokinase-type plasminogen activator receptor, a GPI-linked protein, is localized in caveolae. J Cell Biol 29: 335–344, 1995Google Scholar
  113. 113.
    Wei Y, Yang X, Liu Q, Wilkins JA, Chapman HA: A role for caveolin and the urokinase receptor in integrinmediated adhesion and signaling. J Cell Biol 144: 1285–1294, 1999Google Scholar
  114. 114.
    Aguirre Ghiso JA, Kovalski K, Ossowski L: Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol 147: 89–104, 1999Google Scholar
  115. 115.
    Moro L, Venturino M, Bozzo C, Silengo L, Altruda F, Beguinot L, Tarone G, Defilippi P: Integrins induce activation of EGF receptor: Role in MAP kinase induction and adhesion-dependent cell survival. Embo J 17: 6622–6632, 1998Google Scholar
  116. 116.
    Rabbani SA, Mazar AP, Bernier SM, Haq M, Bolivar I, Henkin J, Goltzman D: Structural requirements for the growth factor activity of the amino-terminal domain of urokinase. J Biol Chem 267: 14151–14156, 1992Google Scholar
  117. 117.
    Sato Y, Rifkin DB: Autocrine activities of basic fibroblast growth factor: Regulation of endothelial cell movement, plasminogen activator synthesis, and DNA synthesis. J Cell Biol 107: 1199–1205, 1988Google Scholar
  118. 118.
    Fibbi G, Ziche M, Morbidelli L, Magnelli L, Del Rosso M: Interaction of urokinase with specific receptors stimulates mobilization of bovine adrenal capillary endothelial cells [published erratumappears in Exp Cell Res 186(1): 196, Jan 1990]. Exp Cell Res 179: 385–395, 1988Google Scholar
  119. 119.
    Sato Y, Tsuboi R, Lyons R, Moses H, Rifkin DB: Characterization of the activation of latent TGF-beta by co-cultures of endothelial cells and pericytes or smooth muscle cells: A self-regulating system. J Cell Biol 111: 757–763, 1990Google Scholar
  120. 120.
    Busso N, Masur SK, Lazega D, Waxman S, Ossowski L: Induction of cell migration by pro-urokinase binding to its receptor: Possible mechanism for signal transduction in human epithelial cells. J Cell Biol 126: 259–270, 1994Google Scholar
  121. 121.
    Nguyen DH, Hussaini IM, Gonias SL: Binding of urokinase-type plasminogen activator to its receptor in MCF-7 cells activates extracellular signal-regulated kinase 1 and 2 which is required for increased cellular motility. J Biol Chem 273: 8502–8507, 1998Google Scholar
  122. 122.
    Naldini L, Vigna E, Bardelli A, Follenzi A, Galimi F, Comoglio PM: Biological activation of pro-HGF (hepatocyte growth factor) by urokinase is controled by a stoichiometric reaction. J Biol Chem 270: 603–611, 1995Google Scholar
  123. 123.
    Odekon LE, Sato Y, Rifkin DB: Urokinase-type plasminogen activator mediates basic fibroblast growth factorinduced bovine endothelial cell migration independent of its proteolytic activity. J Cell Physiol 150: 258–263, 1992Google Scholar
  124. 124.
    Fazioli F, Blasi F: Urokinase-type plasminogen activator and its receptor: New targets for anti-metastatic therapy? Trends Pharmacol Sci 15: 25–29, 1994Google Scholar
  125. 125.
    Chiaradonna F, Fontana L, Iavarone C, Carriero MV, Scholz G, Barone MV, Stopelli MP: Urokinase receptordependent and independent p56/59hck activation state is a molecular switch between myelomonocytic cell motility and adherence. EMBO J 18: 3013–3023, 1999Google Scholar
  126. 126.
    Tang H, Kerins DM, Hao Q, Inagami T, Vaughan DE: The urokinase-type plasminogen activator receptor mediates tyrosine phosphorylation of focal adhesion proteins and activation of mitogen-activated protein kinase in cultured endothelial cells. J Biol Chem 273: 18268–18272, 1998Google Scholar
  127. 127.
    Dumler I, Weis A, Mayboroda OA, Maasch C, Jerke U, Haller H, Gulba DC: The Jak/Stat pathway and urokinase receptor signaling in human aortic vascular smooth muscle cells. J Biol Chem 273: 315–321, 1998Google Scholar
  128. 128.
    Rabbani SA, Gladu J, Mazar AP, Henkin J, Goltzman D: Induction in human osteoblastic cells (SaOS2) of the early response genes fos, jun, and myc by the amino terminal fragment (ATF) of urokinase. J Cell Physiol 172: 137–145, 1997Google Scholar
  129. 129.
    Ploug M, Ellis V: Structure-function relationships in the receptor for urokinase-type plasminogen activator. Comparison to other members of the Ly-6 family and snake venomalpha-neuro toxins. FEBS Lett 349: 163–168, 1994Google Scholar
  130. 130.
    Resnati M, Pallavicini I, Wang JM, Oppenheim J, Serhan CN, Romano M, Blasi F: The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R. Proc Natl Acad Sci USA 99: 1359–1364, 2002Google Scholar
  131. 131.
    Bugge TH, Kombrinck KW, Xiao Q, Holmbäck K, Daugherty CC, Witte DP, Degen JL: Growth and dissemination of Lewis lung carcinoma in plasminogendeficient mice. Blood 90: 4522–4531, 1997Google Scholar
  132. 132.
    Bugge TH, Lund LR, Kombrinck KK, Nielsen BS, Holmbäck K, Drew AF, Flick MJ, Witte DP, Danä K, Degen JL: Reduced metastasis of Polyoma virus middle T antigen-induced mammary cancer in plasminogen-defi-cient mice. Oncogene 16: 3097–3104, 1998Google Scholar
  133. 133.
    Bajou K, Noel A, Gerard RD, Masson V, Brünner N, Holst Hansen C, Skobe M, Fusenig NE, Carmeliet P, Collen D, Foidart JM: Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 4: 923–928, 1998Google Scholar
  134. 134.
    Gutierrez LS, Schulman A, Brito-Robinson T, Noria F, Ploplis VA, Castellino FJ: Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. Cancer Res 60: 5839–5847, 2000Google Scholar
  135. 135.
    Bessler M, Rosti V, Peng Y, Cattoretti G, Notaro R, Ohsako S, Elkon KB, Luzzatto L: Glycosylphosphatidylinositol-linked proteins are required for maintenance of a normal peripheral lymphoid compartment but not for lymphocyte development. Eur J Immunol 32: 2607–2616, 2002Google Scholar
  136. 136.
    Goodson RJ, Doyle MV, Kaufman SE, Rosenberg S: High-affinity urokinase receptor antagonists identified with bacteriophage peptide display. Proc Natl Acad Sci USA 91: 7129–7133, 1994Google Scholar
  137. 137.
    Kobayashi H, Gotoh J, Fujie M, Shinohara H, Moniwa N, Terao T: Inhibition of metastasis of Lewis lung carcinoma by a synthetic peptide within growth factorlike domain of urokinase in the experimental and spontaneous metastasis model. Int J Cancer 57: 727–733, 1994Google Scholar
  138. 138.
    Crowley CW, Cohen RL, Lucas BK, Liu G, Shuman MA, Levinson AD: Prevention of metastasis by inhibition of the urokinase receptor. Proc Natl Acad Sci USA 90: 5021–5025, 1993Google Scholar
  139. 139.
    Lefesvre P, Attema J, van Bekkum D: Adenoviral gene transfer of angiostatic ATF-BPTI inhibits tumor growth. BMC Cancer 2: 17, 2002Google Scholar
  140. 140.
    Kobayashi H, Gotoh J, Hirashima Y, Fujie M, Sugino D, Terao T: Inhibitory effect of a conjugate between human urokinase and urinary trypsin inhibitor on tumor cell invasion in vitro. J Biol Chem 270: 8361–8366, 1995Google Scholar
  141. 141.
    Kobayashi H, Sugino D, She MY, Ohi H, Hirashima Y, Shinohara H, Fujie M, Shibata K, Terao T: A bifunctional hybrid molecule of the amino-terminal fragment of urokinase and domain II of bikunin efficiently inhibits tumor cell invasion and metastasis. Eur J Biochem 253: 817–826, 1998Google Scholar
  142. 142.
    Min HY, Doyle LV, Vitt CR, Zandonella CL, Stratton-Thomas JR, Shuman MA, Rosenberg S: Urokinase receptor antagonists inhibit angiogenesis and primary tumor growth in syngeneic mice. Cancer Res 56: 2428–2433, 1996Google Scholar
  143. 143.
    Bugge TH, Flick MJ, Danton MJ, Daugherty CC, Rämer J, Danä K, Carmeliet P, Collen D, Degen JL: Urokinasetype plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator. Proc Natl Acad Sci USA 93: 5899–5904, 1996Google Scholar
  144. 144.
    Carmeliet P, Moons L, Dewerchin M, Rosenberg S, Herbert JM, Lupu F, Collen D: Receptor-independent role of urokinase-type plasminogen activator in pericellular plasmin and matrix metalloproteinase proteolysis during vascular wound healing in mice. J Cell Biol 140: 233–245, 1998Google Scholar
  145. 145.
    Rockway TW, Nienaber V, Giranda VL: Inhibitors of the protease domain of urokinase-type plasminogen activator. Curr PharmDes 8: 2541–2558, 2002Google Scholar
  146. 146.
    Gladson CL, Cheresh DA: Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells. J Clin Invest 88: 1924–1932, 1991Google Scholar
  147. 147.
    Gladson CL, Pijuan-Thompson V, Olman MA, Gillespie GY, Yacoub IZ: Up-regulation of urokinase and urokinase receptor genes in malignant astrocytoma. Am J Pathol 146: 1150–1160, 1995Google Scholar
  148. 148.
    Kondoh N, Wakatsuki T, Ryo A, Hada A, Aihara T, Horiuchi S, Goseki N, Matsubara O, Takenaka K, Shichita M, Tanaka K, Shuda M, Yamamoto M: Identification and characterization of genes associated with human hepatocellular carcinogenesis. Cancer Res 59: 4990–4996, 1999Google Scholar
  149. 149.
    van der Pluijm G, Sijmons B, Vloedgraven H, van der Bent C, Drijfhout JW, Verheijen J, Quax P, Karperien M, Papapoulos S, Lowik C: Urokinase-receptor/integrin complexes are functionally involved in adhesion and progression of human breast cancer in vivo. Am J Pathol 159: 971–982, 2001Google Scholar
  150. 150.
    Cavallaro U, Soria MR: Targeting plant toxins to the urokinase and alpha 2-macroglobulin receptors. Semin Cancer Biol 6: 269–278, 1995Google Scholar
  151. 151.
    Fabbrini MS, Carpani D, Bello Rivero I, Soria MR: The amino-terminal fragment of human urokinase directs a recombinant chimeric toxin to target cells: Internalization is toxin mediated. Faseb J 11: 1169–1176, 1997Google Scholar
  152. 152.
    Ippoliti R, Lendaro E, Benedetti PA, Torrisi MR, Belleudi F, Carpani D, Soria MR, Fabbrini MS: Endocytosis of a chimera between human pro-urokinase and the plant toxin saporin: An unusual internalization mechanism. Faseb J 14: 1335–1344, 2000Google Scholar
  153. 153.
    Rajagopal V, Kreitman RJ: Recombinant toxins that bind to the urokinase receptor are cytotoxic without requiring binding to the alpha(2)-macroglobulin receptor. J Biol Chem 275: 7566–7573, 2000Google Scholar
  154. 154.
    Vallera DA, Li C, Jin N, Panoskaltsis-Mortari A, Hall WA: Targeting urokinase-type plasminogen activator The urokinase plasminogen activator system in cancer 221 receptor on human glioblastoma tumors with diphtheria toxin fusion protein DTAT. J Natl Cancer Inst 94: 597–606, 2002Google Scholar
  155. 155.
    Liu S, Bugge TH, Leppla SH: Targeting of tumor cells by cell surface urokinase plasminogen activator-dependent anthrax toxin. J Biol Chem 276: 17976–17984, 2001Google Scholar
  156. 156.
    Schmitt M, Harbeck N, Thomssen C, Wilhelm O, Magdolen V, Reuning U, UlmK, Höfler H, Jänicke F, Graeff H: Clinical impact of the plasminogen activation system in tumor invasion and metastasis: Prognostic relevance and target for therapy. Thromb Haemost 78: 285–296, 1997Google Scholar
  157. 157.
    Duffy MJ: Urokinase plasminogen activator and its inhibitor, PAI-1, as prognostic markers in breast cancer: Frompilot to level 1 evidence studies. Clin Chem48: 1194–1197, 2002Google Scholar
  158. 158.
    Janicke F, Prechtl A, Thomssen C, Harbeck N, Meisner C, Untch M, Sweep CGJF, Selbmann H-K, Graeff H, Schmitt M: Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1. J Natl Cancer Inst 93: 913–643, 2001Google Scholar
  159. 159.
    Look MP, van Putten WLJ, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, Kates R, Spyratos F, Ferno M, Eppenberger-Castori S, Sweep CGJF, Ulm K, Peyrat J-P, Martin P-M, Magdelenat H, Brunner N, Duggan C, Lisboa BW, Bendahl P-O, Quillien V, Daver A, Ricolleau G, Meijer-van Gelder ME, Manders P, Fiets WE, Blankenstein MA, Broet P, Romain S, Daxenbichler G, Windbichler G, Cufer T, Borstnar S, Kueng W, Beex LVAM, Klijn JGM, O'Higgins N, Eppenberger U, Janicke F, Schmitt M, Foekens JA: Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 94: 116–643, 2002Google Scholar
  160. 160.
    Hayes D, Bast R, Desch C, Fritsche H, Jr, Kemeny N, Jessup J, Locker G, Macdonald J, Mennel R, Norton L, Ravdin P, Taube S, Winn R: Tumor marker utility grading system: A framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst 88: 1456–1466, 1996Google Scholar
  161. 161.
    Harbeck N, Kates RE, Look MP, Meijer-Van Gelder ME, Klijn JG, Kruger A, Kiechle M, Janicke F, Schmitt M, Foekens JA: Enhanced benefit fromadjuvant chemotherapy in breast cancer patients classified high-risk according to urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (n 1/4 3424). Cancer Res 62: 4617–4622, 2002Google Scholar
  162. 162.
    Riisbro R, Stephens RW, Brünner N, Christensen IJ, Nielsen HJ, Heilmann L, von Tempelhoff GF: Soluble urokinase plasminogen activator receptor in preoperatively obtained plasma from patients with gynecological cancer or benign gynecological diseases. Gynecol Oncol 82: 523–531, 2001Google Scholar
  163. 163.
    Schmidt M, Hoppe F: Increased levels of urokinase receptor in plasma of head and neck squamous cell carcinoma patients. Acta Otolaryngol 119: 949–953, 1999Google Scholar
  164. 164.
    Fernebro E, Madsen RR, Ferno M, Brünner N, Bendahl P, Christensen IJ, Johnson A, Nilbert M: Prognostic importance of the soluble plasminogen activator receptor, suPAR, in plasma from rectal cancer patients. Eur J Cancer 37: 486–491, 2001Google Scholar

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© Kluwer Academic Publishers 2003

Authors and Affiliations

  1. 1.Department of Molecular Biology and Functional Genomics, DIBITUniversità Vita-Salute San RaffaeleMilanItaly
  2. 2.San Raffaele Scientific InstituteMilanItaly

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