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uPAR: a versatile signalling orchestrator

Abstract

The plasminogen system has been implicated in clot lysis, wound healing, tissue regeneration, cancer and many other processes that affect health and disease. The urokinase receptor uPAR was originally thought to assist the directional invasion of migrating cells, but it is now becoming increasingly evident that this proteinase receptor elicits a plethora of cellular responses that include cellular adhesion, differentiation, proliferation and migration in a non-proteolytic fashion.

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Figure 1: Schematic representation of the urokinase receptor.
Figure 2: Schematic representation of the role of uPAR as a proteinase receptor.
Figure 3: Scheme depicting the role of a uPAR–integrin complex as a signalling receptor.
Figure 4: Scheme depicting the role of a uPAR–GPCR complex as a signalling receptor.
Figure 5: Role of uPA and uPAR as deduced from gene-targeting studies in vivo.

References

  1. Collen, D. The plasminogen (fibrinolytic) system. Thromb. Haemost. 82, 259–270 (1999).

    CAS  PubMed  Google Scholar 

  2. Appella, E. et al. The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. J. Biol. Chem. 262, 4437–4440 (1987).

    CAS  PubMed  Google Scholar 

  3. Ploug, M. & Ellis, V. Structure–function relationship in the receptor for urokinase-type plasminogen activator. Comparison to other members of the Ly-6 family and snake venom a-neurotoxins. FEBS Lett. 349, 163–168 (1994).

    CAS  PubMed  Google Scholar 

  4. Behrendt, N., Roenne, E. & Danoe, K. Domain interplay in the urokinase receptor-requirement for the third domain in high affinity ligand binding and demonstration of ligand contact sites in distinct receptor domains. J. Biol. Chem. 271, 22885–22894 (1996).

    CAS  PubMed  Google Scholar 

  5. 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 (1998).

    CAS  PubMed  Google Scholar 

  6. Waltz, D. A. & Chapman, H. A. Reversible cellular adhesion to vitronectin linked to urokinase receptor occupancy. J. Biol. Chem. 269, 14746–14750 (1994).

    CAS  PubMed  Google Scholar 

  7. Loskutoff, D. J., Curriden, S. A., Hu, G. & Deng, G. Regulation of cell adhesion by PAI-1. Apmis. 107, 54–61 (1999).

    CAS  PubMed  Google Scholar 

  8. Nykjær, A. et al. Purified a2-macroglobulin receptor/LDL receptor-related protein binds urokinase-plasminogen activcator inhibitor type-1 complex. Evidence that the a2-macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes. J. Biol. Chem. 267, 14543–14546 (1992).

    PubMed  Google Scholar 

  9. Czekay, R. P., Kuemmel, T. A., Orlando, R. A. & Farquhar, M. G. 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 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Nykjær, A. et al. Recycling of the urokinase receptor during internalization of the uPA–serpin complexes. EMBO J. 16, 2610–2620 (1997).

    PubMed  PubMed Central  Google Scholar 

  11. Sidenius, N., Andolfo, A., Fesce, R. & Blasi, F. Urokinase regulates vitronectin binding in vitro and in vivo by controlling urokinase receptor oligomerization. J. Biol. Chem. 277, 27982–27990 (2002).

    CAS  PubMed  Google Scholar 

  12. Resnati, M. et al. Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect. EMBO J. 15, 1572–1582 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Giancotti, F. G. & Ruoslahti, E. Integrin signaling. Science 285, 1028–1032 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Wei, Y. et al. Regulation of integrin function by the urokinase receptor. Science 273, 1551–1555 (1996). This paper discusses a molecular basis for the mechanism by which uPAR can regulate signalling, by showing a direct interaction between uPAR and integrins.

    CAS  PubMed  Google Scholar 

  15. Yebra, M. et al. Requirement of receptor-bound urokinase-type plasminogen activator for integrin αvβ5-directed cell migration. J. Biol. Chem. 271, 29393–29399 (1996).

    CAS  PubMed  Google Scholar 

  16. Degryse, B., Orlando, S., Resnati, M., Rabbani, S. A. & Blasi, F. Urokinase/urokinase receptor and vitronectin/avb3 integrin induce chemotaxis and cytoskeleton reorganization through different signaling pathways. Oncogene 20, 2032–2043 (2001).

    CAS  PubMed  Google Scholar 

  17. May, A. E. et al. Urokinase receptor (CD87) regulates leukocyte recruitment via β2 integrins in vivo. J. Exp. Med. 188, 1029–1037 (1998). This paper reports a role of uPAR as a signalling receptor in leukocyte recruitment.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Waltz, D. A. et al. Nonproteolytic role for the urokinase receptor in cellular migration in vivo. Am. J. Respir. Cell. Mol. Biol. 22, 316–322 (2000).

    CAS  PubMed  Google Scholar 

  19. Bohuslav, J. et al. Urokinase plasminogen activator receptor, β2-integrins, and Src-kinases within a single receptor complex of human monocytes. J. Exp. Med. 181, 1381–1390 (1995).

    CAS  PubMed  Google Scholar 

  20. Aguirre Ghiso, J. A., 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 (1999).

    CAS  PubMed  Google Scholar 

  21. Carriero, M. V. et al. Urokinase receptor interacts with α(v)β5 vitronectin receptor, promoting urokinase-dependent cell migration in breast cancer. Cancer Res. 59, 5307–5314 (1999).

    CAS  PubMed  Google Scholar 

  22. Tarui, T., Mazar, A. P., Cines, D. B. & Takada, Y. Urokinase receptor (uPAR/CD87) is a ligand for integrin and mediates cell–cell interaction. J. Biol. Chem. 276, 3983–3990 (2000).

    PubMed  Google Scholar 

  23. Simon, D. I. et al. Identification of a urokinase receptor–integrin interaction site. Promiscuous regulator of integrin function. J. Biol. Chem. 275, 10228–10234 (2000).

    CAS  PubMed  Google Scholar 

  24. Wei, Y., Eble, J. A., Wang, Z., Kreidberg, J. A. & Chapman, H. A. Urokinase receptor promotes b1 integrin function through interactions with integrin a3b1. Mol. Biol. Cell 12, 2975–2986 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Liu, D., Aguirre-Ghiso, J. A., 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 (2002).

    CAS  PubMed  Google Scholar 

  26. Montuori, N., Carriero, M. V., Salzano, S., Rossi, G. & Ragno, P. The cleavage of the urokinase receptor regulates its multiple functions. J. Biol. Chem. 2002 Sep 23 (DOI: 10.1074/jbc.M207494200).

  27. Fazioli, F. et al. The urokinase-sensitive region of the urokinase receptor is responsible for its potent chemotactic activity. EMBO J 16, 7279–7286 (1997). This paper identifies the chemotactic epitope of uPAR.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Degryse, B. et al. Src-dependence and pertussis-toxin sensitivity of urokinase receptor-dependent chemotaxis, and cytoskeleton reorganization in rat smooth muscle cells via the urokinase receptor. Blood 94, 649–662 (1999).

    CAS  PubMed  Google Scholar 

  29. Nguyen, D. H. et al. Urokinase-type plasminogen activator stimulates the Ras/extracellular signal-regulated kinase (ERK) signaling pathway and MCF-7 cell migration by a mechanism that requires focal adhesion kinase, Src, and Shc. Rapid dissociation of GRB2/Sps–Shc complex is associated with the transient phosphorylation of ERK in urokinase-treated cells. J. Biol. Chem. 275, 19382–19388 (2000).

    CAS  PubMed  Google Scholar 

  30. Resnati, M. et al. The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R. Proc. Natl Acad. Sci. USA 99, 1359–1364 (2002). This study reports the interaction of uPAR with GPCR.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Le, Y. et al. A new insight in the role of 'old' chemotactic peptide receptor FPR and FPRL1: down-regulation opf chemokine receptors CCR5 and CXCR4. Forum 94, 299–311 (1999).

    Google Scholar 

  32. Simons, K. & Toomre, D. Lipid rafts and signal transduction. Nature Rev. Mol. Cell Biol. 1, 31–39 (2000).

    CAS  Google Scholar 

  33. Wei, Y., Yang, X., Liu, Q., Wilkins, J. A. & Chapman, H. A. A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling. J. Cell Biol. 144, 1285–1294 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Gomez-Mouton, C. et al. Segregation of leading-edge and uropod components into specific lipid rafts during T cell polarization. Proc. Natl Acad. Sci. USA 98, 9642–9647 (2001). This paper shows the existence of two types of glycophospholipid raft (containing GM1 or GM3), and the segregation of uPAR with chemokine receptors in GM3 rafts that are present specifically at the leading edge of a migrating lymphocyte.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Koshelnick, Y., Ehart, M., Hufnagl, P., Heinrich, P. C. & Binder, B. R. Urokinase receptor is associated with the components of the JAK:STAT1 signaling pathway and leads to the activation of this pathway upon receptor clustering in the human kidney epithelial tumor cell line TCL-598. J. Biol. Chem. 272, 28563–28567 (1997).

    CAS  PubMed  Google Scholar 

  36. Weaver, A. M., Hussaini, I. M., Mazar, A., Henkin, J. & Gonias, S. L. Embryonic fibroblasts that are genetically deficient in low density lipoprotein receptor-related protein demonstrate increased activity of the urokinase receptor system and accelerated migration on vitronectin. J. Biol. Chem. 272, 14372–14379 (1997).

    CAS  PubMed  Google Scholar 

  37. Webb, D. J., Nguyen, D. H., Sankovic, M. & Gonias, S. L. The very low density lipoprotein receptor regulates urokinase receptor catabolism and breast cancer cell motility in vitro. J. Biol. Chem. 274, 7412–7420 (1999).

    CAS  PubMed  Google Scholar 

  38. Degryse, B., Sier, C. F. M., Resnati, M., Conese, M. & Blasi, F. PAI-1 inhibits urokinase-induced chemotaxis by internalizing the urokinase receptor. FEBS Lett. 505, 249–254 (2001).

    CAS  PubMed  Google Scholar 

  39. Nykjaer, A. et al. Mannose-6-phosphate/insulin like growth factor II receptor targets the urokinase receptor to lysosomes via a novel binding interaction. J. Cell Biol. 141, 815–828 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Behrendt, N. et al. A urokinase receptor-associated protein with specific collagen binding properties. J. Biol. Chem. 275, 1993–2002 (2000).

    CAS  PubMed  Google Scholar 

  41. Aguirre-Ghiso, J. A., Liu, D., Mignatti, A., Kovalski, K. & Ossowski, L. Urokinase receptor and fibronectin regulate the ERK (MAPK) to p38 (MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol. Biol. Cell 12, 863–879 (2001). This paper identifies the integrin as the target of uPAR in uPAR-dependent cell proliferation, and the requirement of this interaction for cell growth.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Webb, D. J., Nguyen, D. H. & Gonias, S. L. Extracellular signal-regulated kinase functions in the urokinase receptor-dependent pathway by which neutralization of low density lipoprotein receptor-related protein promotes fibrosarcoma cell migration and Matrigel invasion. J. Cell Sci. 113, 123–134 (2000).

    CAS  PubMed  Google Scholar 

  43. Kjoeller, L. & Hall, A. Rac mediates cytoskeletal rearrangements and increased cell motility induced by urokinase-type plasminogen activator receptor binding to vitronectin. J. Cell Biol. 152, 1145–1157 (2001).

    Google Scholar 

  44. Nguyen, D. H. et al. Myosin light chain kinase functions downstream of Ras/ERK to promote migration of urokinase-type plasminogen activator-stimulated cells in an integrin-selective manner. J. Cell Biol. 146, 149–164 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Busso, N., Masur, S. K., 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 (1994).

    CAS  PubMed  Google Scholar 

  46. Myohanen, H. T. et al. Distribution and lateral mobility of the urokinase-receptor complex at the cell surface. J. Histochem. Cytochem. 41, 1291–1301 (1993).

    CAS  PubMed  Google Scholar 

  47. Sitrin, R. G., Pan, P. M., Harper, H. A., Blackwood, R. A. & Todd, R. F. Urokinase receptor (CD87) aggregation triggers phosphoinositide hydrolysis and intracellular calcium mobilization in mononuclear phagocytes. J. Immunol. 163, 6193–6200 (1999).

    CAS  PubMed  Google Scholar 

  48. Sitrin, R. G., Pan, P. M., Blackwood, R. A., Huang, J. & Petty, H. R. Evidence for a signaling partnership between urokinase receptors (cd87) and l-selectin (cd621) in human polymorphonuclear neutrophils. J. Immunol. 166, 4822–4825 (2001).

    CAS  PubMed  Google Scholar 

  49. Le, Y. et al. Amyloid (β)42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1. J. Neurosci. 21, RC123 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Dumler, I. et al. The JAK/STAT pathway and urokinase receptor signaling in human aortin vascular smooth muscle cells. J. Biol. Chem. 273, 315–321 (1998).

    CAS  PubMed  Google Scholar 

  51. Wang, N., Planus, E., Pouchelet, M., Fredberg, J. J. & Barlovatz-Meimon, G. Urokinase receptor mediates mechanical force transfer across the cell surface. Am. J. Physiol. 268, C1062–C1066 (1995).

    CAS  PubMed  Google Scholar 

  52. Kusch, A. et al. Urokinase stimulates human vascular smooth muscle cells migration via a phosphatidylinositol 3-kinase-tyk2 interaction. J. Biol. Chem. 275, 39466–39473 (2000).

    CAS  PubMed  Google Scholar 

  53. 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 (2000).

    CAS  PubMed  Google Scholar 

  54. Stepanova, V. et al. Urokinase-dependent human vascular smooth muscle cells adhesion requires selective vitronectin phorphorylation by ecto-protein kinase CK2. J. Biol. Chem. 277, 10265–10272 (2002).

    CAS  PubMed  Google Scholar 

  55. Simon, D. I. et al. Mac-1 (CD11b/CD18) and the urokinase receptor (CD87) form a functional unit on monocytic cells. Blood 88, 3185–3194 (1996).

    CAS  PubMed  Google Scholar 

  56. Nusrat, A. R. & Chapman, H. A. An autocrine role for urokinase in phorbol ester-mediated differentiation of myeloid cell lines. J. Clin. Invest. 87, 1091–1097 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Ferias-Eisner, R. et al. Thye urokinase plasminogen activator receptor (uPAR) is preferentially induced by nerve growth factors in PC12 pheomocromocytoma cells and is required for NGF-driven differentiation. J. Neurosci. 20, 230–239 (2000).

    Google Scholar 

  58. Rabbani, S. A. et al. Structural requirements for the growth factor activity of the amino-terminal domain of urokinase. J. Biol. Chem. 267, 14151–14156 (1992).

    CAS  PubMed  Google Scholar 

  59. Kirchheimer, J. C., Wojta, J., Christ, G., Hienert, G. & Binder, B. R. Proliferation of a human epidermal tumor cell line stimulated by urokinase. FASEB J. 1, 125–128 (1987).

    CAS  PubMed  Google Scholar 

  60. Yu, W., Kim, J. & Ossowski, L. Reduction in surface urokinase receptor forces malignant cells into a protracted state of dormancy. J. Cell Biol. 137, 767–777 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Carmeliet, P. et al. 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 (1998). This paper provides a possible explanation for the redundant role of uPAR as protease receptor, in part because uPA binds other ECM components.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Chiaradonna, F. et al. Urokinase receptor-dependent and -independent p56/59hck activation state is a molecular switch between myelomonocytic cell motility and adherence. EMBO J. 11, 3013–3023 (1999).

    Google Scholar 

  63. Kook, Y. H., Adamski, J., Zelent, A. & Ossowski, L. The effect of antisense inhibition of urokinase receptor in human squamous cell carcinoma on malignancy. EMBO J. 13, 3983–3991 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Luttun, A., Dewerchin, M., Collen, D. & Carmeliet, P. The role of proteinases in angiogenesis, heart development, restenosis, atherosclerosis, myocardial ischemia, and stroke: insights from genetic studies. Curr. Atheroscler. Rep. 2, 407–416 (2000).

    CAS  PubMed  Google Scholar 

  65. Degen, J. L. Genetic interactions between the coagulation and fibrinolytic systems. Thromb. Haemost. 86, 130–137 (2001).

    CAS  PubMed  Google Scholar 

  66. Eitzman, D. T. & Ginsburg, D. Of mice and men. The function of plasminogen activator inhibitors (PAIs) in vivo. Adv. Exp. Med. Biol. 425, 131–141 (1997).

    CAS  PubMed  Google Scholar 

  67. Carmeliet, P. et al. Physiological consequences of loss of plasminogen activator gene function in mice. Nature 369, 419–424 (1994). The first study of a proteinase knockout in mice, reporting the crucial role of tPA and uPA in normal health.| PubMed |

    Google Scholar 

  68. Bugge, T. H. et al. The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility. J. Biol. Chem. 270, 16886–16894 (1995). This paper reports the normal phenotype of uPAR-deficient mice.

    CAS  PubMed  Google Scholar 

  69. Dewerchin, M. et al. Generation and characterization of urokinase receptor-deficient mice. J. Clin. Invest. 97, 870–878 (1996). This paper reports the normal phenotype of uPAR-deficient mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Ploplis, V. A. et al. Effects of disruption of the plasminogen gene on thrombosis, growth and health in mice. Circulation 92, 2585–2593 (1995).

    CAS  PubMed  Google Scholar 

  71. Bugge, T. H., Flick, M. J., Daugherty, C. C. & Degen, J. L. Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction. Genes Dev. 9, 794–807 (1995).

    CAS  PubMed  Google Scholar 

  72. Bugge, T. H. et al. Loss of fibrinogen rescues mice from pleiotropic effects of plasminogen deficiency. Cell 87, 709–719 (1996).

    CAS  PubMed  Google Scholar 

  73. Bugge, T. H. et al. Urokinase-type 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 (1996). This study reports that uPAR is redundant as a protease receptor in fibrin surveillance.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Carmeliet, P. & Collen, D. Development and disease in proteinase-deficient mice: role of the plasminogen, matrix metalloproteinase and coagulation system. Thromb. Res. 91, 255–285 (1998).

    CAS  PubMed  Google Scholar 

  75. Carmeliet, P. et al. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nature Genet. 17, 439–444 (1997). This paper reports that matrix metalloproteinases are activated by uPA-generated plasmin in vivo.

    CAS  PubMed  Google Scholar 

  76. Moons, L. et al. Reduced transplant arteriosclerosis in plasminogen-deficient mice. J. Clin. Invest. 102, 1788–1797 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Carmeliet, P. et al. Urokinase but not tissue plasminogen activator mediates arterial neointima formation in mice. Circ. Res. 81, 829–839 (1997).

    CAS  PubMed  Google Scholar 

  78. Heymans, S. et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nature Med. 5, 1135–1142 (1999). This paper reports that loss of uPA, but not uPAR, prevents destruction of the ischaemic myocardium, thereby showing a redundant role of uPAR as a proteinase receptor.

    CAS  PubMed  Google Scholar 

  79. Lund, L. R. et al. Functional overlap between two classes of matrix-degrading proteases in wound healing. EMBO J. 18, 4645–4656 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Romer, J. et al. Impaired wound healing in mice with a disrupted plasminogen gene. Nature Med. 2, 287–292 (1996).

    CAS  PubMed  Google Scholar 

  81. Bajou, K. et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nature Med. 4, 923–928 (1998).

    CAS  PubMed  Google Scholar 

  82. Bajou, K. et al. The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. J. Cell Biol. 152, 777–784 (2001). This paper reports a redundant role of host uPAR in tumour vascularization.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Carmeliet, P., Moons, L., Ploplis, V., Plow, E. & Collen, D. Impaired arterial neointima formation in mice with disruption of the plasminogen gene. J. Clin. Invest. 99, 200–208 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Levi, M. et al. Deficiency of urokinase-type plasminogen activator-mediated plasmin generation impairs vascular remodeling during hypoxia-induced pulmonary hypertension in mice. Circulation 103, 2014–2020 (2001).

    CAS  PubMed  Google Scholar 

  85. Soriano, S. G. et al. Mice deficient in Mac-1 (CD11b/CD18) are less susceptible to cerebral ischemia/reperfusion injury. Stroke 30, 134–139 (1999).

    CAS  PubMed  Google Scholar 

  86. Gyetko, M. R. et al. Urokinase receptor-deficient mice have impaired neutrophil recruitment in response to pulmonary Pseudomonas aeruginosa infection. J. Immunol. 165, 1513–1519 (2000). This paper reports a role of uPAR as a signalling receptor in neutrophil recruitment.

    CAS  PubMed  Google Scholar 

  87. Metzler, B. et al. Mouse model of myocardial remodelling after ischemia: role of intercellular adhesion molecule-1. Cardiovasc. Res. 49, 399–407 (2001).

    CAS  PubMed  Google Scholar 

  88. Bunting, M., Harris, E. S., McIntyre, T. M., Prescott, S. M. & Zimmerman, G. A. Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving β2 integrins and selectin ligands. Curr. Opin. Hematol. 9, 30–35 (2002).

    PubMed  Google Scholar 

  89. Gyetko, M. R. et al. Antigen-driven lymphocyte recruitment to the lung is diminished in the absence of urokinase-type plasminogen activator (uPA) receptor, but is independent of uPA. J. Immunol. 167, 5539–5542 (2001).

    CAS  PubMed  Google Scholar 

  90. Gyetko, M. R., Todd, R. F., Wilkinson, C. C. & Sitrin, R. G. The urokinase receptor is required for human monocyte chemotaxis in vitro. J. Clin. Invest. 93, 1380–1387 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Rijneveld, A. W. et al. Urokinase receptor is necessary for adequate host defense against pneumococcal pneumonia. J. Immunol. 168, 3507–3511 (2002).

    CAS  PubMed  Google Scholar 

  92. Gyetko, M. et al. Urokinase is required for the pulmonary inflammatory response to Cryptococcus neoformans. A murine transgenic model. J. Clin. Invest. 97, 1818–1826 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Jones, S. P. et al. Leukocyte and endothelial cell adhesion molecules in a chronic murine model of myocardial reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 279, 196–201 (2000).

    Google Scholar 

  94. Alfano, M., Sidenius, N., Panzeri, B., Blasi, F. & Poli, G. Urokinase–urokinase receptor interaction mediates an inhibitory signal for HIV-1 replication. Proc. Natl Acad. Sci. USA 99, 8862–8867 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Speth, C., Pichler, I., Stockl, G., Mair, M. & Dierich, M. P. Urokinase plasminogen activator receptor (uPAR; CD87) expression on monocytic cells and T cells is modulated by HIV-1 infection. Immunobiology 199, 152–162 (1998).

    CAS  PubMed  Google Scholar 

  96. Coleman, J. L., Gebbia J. A. & Benach J. L. Borrelia burgdorferi and other bacterial products induce expression and release of the urokinase receptor. J. Immunol. 166, 473–480 (2001).

    CAS  PubMed  Google Scholar 

  97. Sidenius, N. et al. Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection. Blood 96, 4091–4095 (2000).

    CAS  PubMed  Google Scholar 

  98. Florquin, S. et al. Release of urokinase plasminogen activator receptor during urosepsis and endotoxemia. Kidney Int. 59, 2054–2061 (2001).

    CAS  PubMed  Google Scholar 

  99. Xue, W., Hashimoto, K. & Toi, Y. Functional involvement of urokinase-type plasminogen activator receptor in pemphigus acantholysis. J. Cutan Pathol. 25, 469–474 (1998).

    CAS  PubMed  Google Scholar 

  100. Del Rosso, M., Fibbi, G. & Matucci Cerinic, M. The urokinase-type plasminogen activator system and inflammatory joint diseases. Clin. Exp. Rheumatol. 17, 485–498 (1999).

    CAS  PubMed  Google Scholar 

  101. Walker, D. G., Lue, L. F. & Beach, T. G. Increased expression of the urokinase plasminogen-activator receptor in amyloid β peptide-treated human brain microglia and in AD brains. Brain Res. 926, 69–79 (2002).

    CAS  PubMed  Google Scholar 

  102. Okada, S. S. et al. Native atherosclerosis and vein graft arterialization: association with increased urokinase receptor expression in vitro and in viv. Thromb. Haemost. 80, 140–147 (1998).

    CAS  PubMed  Google Scholar 

  103. Solberg, H., Ploug, M., Hoyer-Hansen, G., Nielsen, B. S. & Lund, L. R. The murine receptor for urokinase-type plasminogen activator is primarily expressed in tissues actively undergoing remodeling. J. Histochem. Cytochem. 49, 237–246 (2001).

    CAS  PubMed  Google Scholar 

  104. Bisgaard, H. C., Santoni-Rugiu, E., Nagy, P. & Thorgeirsson, S. S. Modulation of the plasminogen activator/plasmin system in rat liver regenerating by recruitment of oval cells. Lab. Invest. 78, 237–246 (1998).

    CAS  PubMed  Google Scholar 

  105. Stephens, R. W. et al. Plasma urokinase receptor levels in patients with colorectal cancer: relationship to prognosis. J. Natl Cancer Inst. 91, 869–874 (1999). This paper shows that, in colon carcinoma patients, high serum levels of uPAR predict poor survival.

    CAS  PubMed  Google Scholar 

  106. Crowley, C. W. et al. Prevention of metastasis by inhibition of the urokinase receptor. Proc. Natl Acad. Sci. USA 90, 5021–5025 (1993). In a human xenografted tumour model, co-expression of inhibitors of the uPA–uPAR interaction block metastasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Min, H. Y. et al. Urokinase receptor antagonists inhibit angiogenesis and primary tumor growth in syngeneic mice. Cancer Res. 56, 2428–2433 (1996). Interference with the uPA—uPAR interaction blocks tumour angiogenesis and growth.

    CAS  PubMed  Google Scholar 

  108. Stoppelli, M. P. et al. Autocrine saturation of pro-urokinase receptor on human A431 cells. Cell 45, 675–684 (1986).

    CAS  PubMed  Google Scholar 

  109. Pyke, C. et al. Urokinase-type plasminogen activator is expressed in stromal cells and its receptor in cancer cells at invasive foci in human colon adenocarcinoma. Am. J. Pathol. 138, 1059–1067 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Brunner, N. et al. The urokinase plasminogen activator receptor in blood from healthy individuals and patients with cancer. Apmis. 107, 160–167 (1999).

    CAS  PubMed  Google Scholar 

  111. Lakka, S. S. et al. Adenovirus-mediated antisense urokinase-type plasminogen activator receptor gene transfer reduces tumor cell invasion and metastasis in non-small cell lung cancer cell lines. Clin. Cancer Res. 7, 1087–1093 (2001).

    CAS  PubMed  Google Scholar 

  112. Ploug, M. et al. Peptide-derived antagonists of the urokinase receptor. Affinity maturation by combinatorial chemistry, identification of functional epitopes, and inhibitory effect on cancer cell intravasation. Biochemistry 40, 12157–12168 (2001).

    CAS  PubMed  Google Scholar 

  113. Pepper, M. S. Role of the matrix metalloproteinase and plasminogen activator–plasmin systems in angiogenesis. Arterioscler. Thromb. Vasc. Biol. 21, 1104–1117 (2001).

    CAS  PubMed  Google Scholar 

  114. Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    CAS  PubMed  Google Scholar 

  115. Jain, R. K. & Carmeliet, P. F. Vessels of death or life. Sci. Am. 285, 38–45 (2001).

    CAS  PubMed  Google Scholar 

  116. Thewes, M., Elsner, E., Wessner, D., Engst, R. & Ring, J. The urokinase plasminogen activator system in angiosarcoma, Kaposi's sarcoma, granuloma pyogenicum, and angioma: an immunohistochemical study. Int. J. Dermatol. 39, 188–191 (2000).

    CAS  PubMed  Google Scholar 

  117. Fibbi, G. et al. Urokinase-dependent angiogenesis in vitro and diacylglycerol production are blocked by antisense oligonucleotides against the urokinase receptor. Lab. Invest. 78, 1109–1119 (1998).

    CAS  PubMed  Google Scholar 

  118. Li, H. et al. Adenovirus mediated delivery of a uPA/uPAR antagonist suppresses angiogenesis-dependent tumor growth and dissemination in mice. Gene Ther. 5, 1105–1113 (1998).

    CAS  PubMed  Google Scholar 

  119. Harbeck, N. et al. Clinical relevance of the plasminogen activator inhibitor type 1 — a multifaceted proteolytic factor. Onkologie 24, 238–244 (2001).

    CAS  PubMed  Google Scholar 

  120. Lambert, V. et al. Influence of plasminogen activator inhibitor type-1 on choroidal neovascularization. FASEB J. 15, 1021–1027 (2001).

    CAS  PubMed  Google Scholar 

  121. Gutierrez, L. S. et al. 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 (2000).

    CAS  PubMed  Google Scholar 

  122. McMahon, G. A. et al. Plasminogen activator inhibitor-1 regulates tumor growth and angiogenesis. J. Biol. Chem. 276, 33964–33968 (2001).

    CAS  PubMed  Google Scholar 

  123. Stefansson, S. et al. Inhibition of angiogenesis in vivo by plasminogen activator inhibitor-1. J. Biol. Chem. 276, 8135–8141 (2001).

    CAS  PubMed  Google Scholar 

  124. Devy, L. et al. The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J. 16, 147–154 (2002).

    CAS  PubMed  Google Scholar 

  125. Ossowski, L. & Aguirre Ghiso, J. A. Urokinase receptor and integrin partnership: coordination of signaling for cell adhesion, migration and growth. Curr. Opin. Cell Biol. 12, 613–620 (2000). A thoughtful survey of the signalling pathways that are activated by uPAR.

    CAS  PubMed  Google Scholar 

  126. Carmeliet, P. & Collen, D. Transgenic mouse models in angiogenesis and cardiovascular disease, J Pathol. 190, 387–405 (2000).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank all of their collaborators who have contributed to these studies, R. Farookhi, L. Ossowski, R. Pardi for their comments on the manuscript, and M. Ploug for his comments. Work in F.B.'s laboratory was carried out under the auspices of the Excellence Center in Cell Differentiation, Università Vita Salute San Raffaele, Milano, Italy and was sponsored by the Italian Association for Cancer Research (AIRC), the Italian Ministry of University and Research and the European Union (Vth Framework programme). Work in P.C.'s laboratory was sponsored by the Geconcerteerde Ouderzoeksactie (Concerted Research Action) and Inter-Universitary Attraction Poles.

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DATABASES

LocusLink

CD18

CD62L

EGF

Fgr

FPR

FPRL1

Hck

Lck

MAPK

MCP1

MEK

MLCK

MMPs

PI3K

p38 MAPK

PKC

SDF1-α

TGF-β1

TYK2

uPAR

vitronectin

α2-antiplasmin

OMIM

Alzheimer's disease

multiple sclerosis

FURTHER INFORMATION

Francesco Blasi's laboratory

Peter Carmeliet's laboratory

Glossary

ZYMOGEN

A proteolytically inactive precursor of a protease. Most of these proteases contain a prodomain at the amino terminus, which keeps the corresponding enzyme inactive. The prodomain is removed by endoproteolysis. This can be mediated by other proteases (so zymogens and their activating proteases are often members of a proteolytic cascade), or by autoproteolysis.

GPI ANCHOR

The function of this post-translational modification is to attach proteins to the exoplasmic leaflet of membranes, possibly to specific domains therein. The anchor is made of one molecule of phosphatidylinositol to which a carbohydrate chain is linked through the C-6 hydroxyl of the inositol, and is linked to the protein through an ethanolamine phosphate moiety.

TROPHOBLAST CELLS

Cells of the extra-embryonic epithelial tissue, which is crucial for formation of the placenta.

KERATINOCYTES

Differentiated epithelial cells of the skin.

OVAL PROGENITOR CELLS

Oval cells are bipotential live cells that are able to differentiate into hepatocytes and cholangiocytes.

THROMBOLYSIS

The dissolution of a blood clot (thrombus) as a result of physiological or pharmacological action.

SERPIN FAMILY

A superfamily of serine proteinase inhibitors that show a high degree of homology. Although many inhibit serine proteases, some, such as ovalbumin and angiotensinogen, have no inhibitory function.

KAPOSI'S SARCOMA

An angiogenic tumour that is composed of endothelial and spindle cells (elongated fibroblast-like-shaped cells that usually express endothelial markers).

PERTUSSIS TOXIN

A mixture of proteins that is produced by Bordetella pertussis. It activates Gi proteins by catalysing ADP ribosylation of the α-subunit.

LAMELLIPODIA

Flattened, sheet-like structures that are composed of a crosslinked F-actin meshwork and project from the surface of a cell. They are often associated with cell migration.

RHO FAMILY GTPASES

Ras-related GTPases that are involved in controlling the polymerization of actin.

UROPOD

The slightly narrow trailing edge of a polarized, migrating cell.

LEUKOCYTE ROLLING

The first of a two-step mechanism by which white blood cells adhere to the endothelium. Before they adhere firmly (the second step, which is integrin-mediated), leukocytes 'roll' inside vessels, making transient attachments that are mediated primarily by selectins.

DOMINANT NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

PHORBOL ESTERS

Polycyclic esters that are isolated from croton oil. The most common is phorbol myristoyl acetate (PMA, also known as 12,13-tetradecanoyl phorbol acetate or TPA). They are potent co-carcinogens or tumour promoters because they mimic diacylglycerol, thereby irreversibly activating protein kinase C.

PC12 CELLS

A clonal line of rat adrenal pheochromocytoma cells, which respond to nerve growth factor and can synthesize, store and secrete catecholamines, much like sympathetic neurons. PC12 cells contain small, clear synaptic-like vesicles and larger, dense core granules.

CHORIOALLANTOIC MEMBRANE

An extremely vascular envelope that is created by the fusion of the allantoic membrane with the chorion. It functions in the exchange of wastes and metabolites in the embryo.

STENT

A splint that is placed inside a duct or a canal.

ANEURYSMAL DILATION

Dilation that occurs as the result of an aneurysm — a balloon-like swelling in the wall of an artery.

RESTENOSIS

A re-narrowing or blockage of an artery at the same site in which treatment, such as an angioplasty or stent procedure, has already taken place.

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Blasi, F., Carmeliet, P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 3, 932–943 (2002). https://doi.org/10.1038/nrm977

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