The urokinase-type plasminogen activator and the generation of inhibitors of urokinase activity and signaling

Current Pharmaceutical Design

Volumn 17, Issue 19, 2011, Pages 1944-1961

  Carriero, Maria Vincenza ^a   Stoppelli, Maria Patrizia ^b  

^a NATIONAL CANCER INSTITUTE   (Italy)

^b INSTITUTE OF GENETICS AND BIOPHYSICS ADRIANO BUZZATI TRAVERSO   (Italy)

Author keywords

Cell invasion; Cell migration; Plasminogen activation inhibitors; Urokinase cryptic activities; Urokinase signaling inhibitors

Indexed keywords

ALPHAVBETA5 INTEGRIN; ANTINEOPLASTIC AGENT; GLYCOSYLPHOSPHATIDYLINOSITOL; PLASMINOGEN ACTIVATOR INHIBITOR; UK 122; UNCLASSIFIED DRUG; UROKINASE; UROKINASE RECEPTOR; VOLOCIXIMAB; WX 671;

AMINO TERMINAL SEQUENCE; ANTINEOPLASTIC ACTIVITY; CATALYSIS; CELL ADHESION; CELL INVASION; CELL MIGRATION; CELL PROLIFERATION; CELL SURFACE; CELL SURVIVAL; ENZYME BLOOD LEVEL; GENE CONTROL; GENE EXPRESSION; HUMAN; MOLECULAR INTERACTION; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PLASMINOGEN ACTIVATION; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN INTERACTION; PROTEIN STRUCTURE; REVIEW; SIGNAL TRANSDUCTION;

DRUG DESIGN; GENE EXPRESSION REGULATION; HUMANS; NEOPLASMS; RECEPTORS, UROKINASE PLASMINOGEN ACTIVATOR; SIGNAL TRANSDUCTION; UROKINASE-TYPE PLASMINOGEN ACTIVATOR;

EID: 80051691520     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161211796718143     Document Type: Review

References (249)

1. MacFarlane RG, Pillig, J. Fibrinolytic activity of normal urine. Nature 1947; 159: 779.
2. Williams JRB. Brit J Exptl Pathol 1951; 32.
3. Lesuk A, Terminiello L, Traver jh. Crystalline human urokinase: some properties. Science. 1965;147: 880-882.
4. Lund LR, Green KA, Stoop AA, et al. Plasminogen activation independent of uPA and tPA maintains wound healing in genedeficient mice. EMBO J 2006; 25: 2686-2697.
5. Collen D, Lijnen HR. Tissue-type plasminogen activator: a historical perspective and personal account. J Thromb Haemost 2004; 4: 541-546.
6. Ploug M, Behrendt N, Løber D, Danø K. Protein structure and membrane anchorage of the cellular receptor for urokinase-type plasminogen activator. Semin Thromb Hemost 1991; 17: 183-893.
7. Franco P, Vocca I, Carriero MV, et al. Activation of urokinase receptor by a novel interaction between the connecting peptide region of urokinase and alpha v beta 5 integrin. J Cell Sci 2006; 119: 3424-3434.
8. Wei Y, Lukasev M, Simon DI, Bodary SC, Rosenberg S, Doyle MV, Chapman HA. Science 1996; 273:1551-1555.
9. Kjøller L, Hall A. Rac mediates cytoskeletal rearrangements and increased cell motility induced by urokinase-type plasminogen activator receptor binding to vitronectin. J Cell Biol 2001;152:1145-1157.
10. Sidenius N, Blasi F. The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy. Cancer Metastasis Rev 2003; 22: 205-222.
11. Binder BR, Mihaly J, Prager GW. UPAR-uPA-PAI-1 interactions and signaling: a vascular biologist's view. Thromb Haemost 2007; 97: 336-342.
12. 92 chemotactic sequence. J Thromb Haemost 2010; 8: 2789-2799.
13. Alfano D, Iaccarino I, Stoppelli MP. Urokinase signaling through its receptor protects against anoikis by increasing BCL-xL expression levels. J Biol Chem 2006; 28: 17758-17767.
14. Lester RD, Jo M, Montel V, Takimoto S, Gonias SL. UPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells. J Cell Biol 2007;178:425-436.
15. Conn EM, Botkjaer KA, Kupriyanova TA, Andreasen PA, Deryugina EI, Quigley JP. Comparative analysis of metastasis variants derived from human prostate carcinoma cells: roles in intravasation of VEGF-mediated angiogenesis and uPA-mediated invasion. Am J Pathol 2009;175:1638-652.
16. Andreasen PA, Kjoller L, Christensen L, Duffy MJ. The urokinasetype plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997; 72: 1-22.
17. Andreasen PA, Egelund R, Petersen HH. The plasminogen activation system in tumor growth, invasion, and metastasis. Cell Mol Life Sci 2000; 57: 25-40.
18. Shapiro RL, Duquette JG, Roses DF, et al. Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and wild-type mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals. Cancer Res 1996; 56: 3597-3604.
19. Almholt K, Lund LR, Rygaard J, et al. Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice. Int J Cancer 2005; 113: 525-532.
20. Danø K, Rømer J, Nielsen BS, et al. Cancer invasion and tissue remodeling-cooperation of protease systems and cell types. APMIS 1999; 107: 120-127.
21. Danø K, Behrendt N, Høyer-Hansen G, et al. Plasminogen activation and cancer. Thromb Haemost 2005; 93: 676-681.
22. Mueller MM, Fusenig NE. Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 2004; 4: 839-849.
23. Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des 2004; 10: 39-49.
24. Schmitt M, Jänicke F, Graeff H. Tumour-associated fibrinolysis: the prognostic relevance of plasminogen activators uPA and tPA in human breast cancer. Blood Coagul Fibrinolysis 1990; 1: 695-702.
25. Mengele K, Napieralski R, Magdolen V, et al. Characteristics of the level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1. Expert Rev Mol Diagn 2010; 10:947-962.
26. Shariat SF, Roehrborn CG, McConnell JD, et al. Association of the circulating levels of the urokinase system of plasminogen activation with the presence of prostate cancer and invasion, progression, and metastasis. J Clin Oncol 2007; 25: 349-355.
27. Mustjoki S, Sidenius N, Sier CF, et al. Soluble urokinase receptor levels correlate with number of circulating tumor cells in acute myeloid leukemia and decrease rapidly during chemotherapy. Cancer Res 2000; 60: 7126-7132.
28. Rigolin GM, Tieghi A, Ciccone M, et al. Soluble urokinase-type plasminogen activator receptor (suPAR) as an independent factor predicting worse prognosis and extra-bone marrow involvement in multiple myeloma patients. Br J Haematol 2003; 120: 953-959.
29. Graf M, Reif S, Hecht K, Pelka-Fleischer R, Pfister K, Schmetzer H. High expression of urokinase plasminogen activator receptor (UPA-R) in acute myeloid leukemia (AML) is associated with worse prognosis. Am J Hematol 2005; 79: 26-35.
30. Shariat SF, Monoski MA, Andrews B, Wheeler TM, Lerner SP, Slawin KM. Association of plasma urokinase-type plasminogen activator and its receptor with clinical outcome in patients undergoing radical cystectomy for transitional cell carcinoma of the bladder. Urology 2003; 61: 1053-1058.
31. El-Kott AF, Khalil AM, El-Kenawy Ael-M. Immunohistochemical expressions of uPA and its receptor uPAR and their prognostic significantin urinary bladder carcinoma. Int Urol Nephrol 2004; 36: 417-423.
32. Del Vecchio S, Stoppelli MP, Carriero MV, et al. Human urokinase receptor concentration in malignant and benign breast tumors by in vitro quantitative autoradiography: comparison with urokinase levels. Cancer Res 1993; 53: 3198-3206.
33. Foekens JA, Peters HA, Look MP, et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res 2000; 60: 636-643.
34. Riisbro R, Christensen IJ, Piironen T, et al. Prognostic significance of soluble urokinase plasminogen activator receptor in serum and cytosol of tumor tissue from patients with primary breast cancer. Clin Cancer Res 2002; 8:1132-1141.
35. Pierga JY, Bonneton C, Magdelénat H, et al. Real-time quantitative PCR determination of urokinase-type plasminogen activator receptor (uPAR) expression of isolated micrometastatic cells from bone marrow of breast cancer patients. Int J Cancer 2005; 114: 291-298.
36. Meijer-van Gelder ME, Look MP, et al. Urokinase-type plasminogen activator system in breast cancer: association with tamoxifen therapy in recurrent disease. Cancer Res 2004; 64: 4563-4568.
37. 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 1991; 138: 1059-1067.
38. Lomholt AF, Christensen IJ, Høyer-Hansen G, Nielsen HJ. Prognostic value of intact and cleaved forms of the urokinase plasminogen activator receptor in a retrospective study of 518 colorectal cancer patients. Acta Oncol 2010; 49: 805-811.
39. Heiss MM, Babic R, Allgayer H, et al. Tumor-associated proteolysis and prognosis: new functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system. J Clin Oncol 1995; 13: 2084-2093.
40. Heiss MM, Simon EH, Beyer BC, et al. Minimal residual disease in gastric cancer: evidence of an independent prognostic relevance of urokinase receptor expression by disseminated tumor cells in the bone marrow. J Clin Oncol 2002; 20: 2005-2016.
41. Kita Y, Fukagawa T, Mimori K, et al. Expression of uPAR mRNA in peripheral blood is a favourite marker for metastasis in gastric cancer cases. Br J Cancer 2009; 100: 153-159.
42. Yamamoto M, Sawaya R, Mohanam S, et al. Expression and localization of urokinase-type plasminogen activator receptor in human gliomas. Cancer Res 1994; 54: 5016-5020.
43. Salajegheh M, Rudnicki A, Smith TW. Expression of urokinasetype plasminogen activator receptor (uPAR) in primary central nervous system neoplasms. Appl Immunohistochem Mol Morphol 2005; 13: 184-189.
44. Morita Y, Hayashi Y, Wang Y, et al. Expression of urokinase-type plasminogen activator receptor in hepatocellular carcinoma. Hepatology 1997; 25: 856-861.
45. Zhou L, Hayashi Y, Itoh T, Wang W, Rui J, Itoh H. Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 and -2 in hepatocellular carcinoma. Pathol Int 2000; 50: 392-397.
46. Pedersen H, Brünner N, Francis D, et al. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res 1994; 54: 4671-4675.
47. Pappot H, Høyer-Hansen G, Rønne E, et al. Elevated plasma levels of urokinase plasminogen activator receptor in non-small cell lung cancer patients. Eur J Cancer 1997;33:867-872.
48. Wang L, Madigan MC, Chen H, et al. Expression of urokinaseplasminogen activator and its receptor in advanced epithelial ovarian cancer patients. Gynecol Oncol 2009;114: 265-272.
49. Pedersen N, Schmitt M, Rønne E, et al. A ligand-free, soluble urokinase receptor is present in the ascitic fluid from patients with ovarian cancer. J Clin Invest 1993; 92: 2160-7.
50. Henic E, Borgfeldt C, Christensen IJ, Casslén B, Høyer-Hansen G. Cleaved forms of the urokinase plasminogen activator receptor in plasma have diagnostic potential and predict postoperative survival in patients with ovarian cancer. Clin Cancer Res 2008; 14:5785-5793.
51. Bacchiocchi R, Rubini C, Pierpaoli E, et al. Prognostic value analysis of urokinase-type plasminogen activator receptor in oral squamous cell carcinoma: an immunohistochemical study. BMC Cancer 2008; 8: 220.
52. Xue A, Scarlett CJ, Jackson CJ, Allen BJ, Smith RC. Prognostic significance of growth factors and the urokinase-type plasminogen activator system in pancreatic ductal adenocarcinoma. Pancreas 2008; 36: 160-167.
53. Hildenbrand R, Niedergethmann M, Marx A, et al. Amplification of the urokinase-type plasminogen activator receptor (uPAR) gene in ductal pancreatic carcinomas identifies a clinically high-riskgroup. Am J Pathol 2009; 174: 2246-2253.
54. Miyake H, Hara I, Yamanaka K, Arakawa S, Kamidono S. Elevation of urokinase-type plasminogen activator and its receptor densities as new predictors of disease progression and prognosis in men with prostate cancer. Int J Oncol 1999; 14: 535-541.
55. Almasi CE, Brasso K, Iversen P, et al. Prognostic and predictive value of intact and cleaved forms of the urokinase plasminogen activator receptor in metastatic prostate cancer. Prostate 2011; 71: 899-907.
56. Bifulco K, Longanesi-Cattani I, Masucci MT, et al. Involvement of the soluble urokinase receptor in chondrosarcoma cell mobilization. Sarcoma 2011; 2011: 842842.
57. Taubert H, Würl P, Greither T, et al. Co-detection of members of the urokinase plasminogen activator system in tumour tissue and serum correlates with a poor prognosis for soft-tissue sarcoma patients. Br J Cancer 2010; 102: 731-737.
58. Ulisse S, Baldini E, Mottolese M, et al. Increased expression of urokinase plasminogen activator and its cognate receptor in human seminomas. BMC Cancer 2010; 10: 151.
59. Ulisse S, Baldini E, Sorrenti S, et al. High expression of the urokinase plasminogen activator and its cognate receptor associates with advanced stages and reduced disease-free interval in papillarythyroid carcinoma. J Clin Endocrinol Metab 2011; 96: 504-508.
60. Mazar AP. Urokinase plasminogen activator receptor choreographs multiple ligand interactions: implications for tumor progression and therapy. Clin Cancer Res 2008; 14: 5649-5655.
61. Carriero MV, Franco P, Votta G, et al. Regulation of cell migration and invasion by specific modules of uPA: mechanistic insights and specific inhibitors. Curr Drug Targets 2011; in press.
62. Blasi F, Sidenius N. The urokinase receptor: focused cell surface proteolysis, cell adhesion and signaling. FEBS Lett 2010; 584:1923-1930.
63. May AE, Kanse SM, Lund LR, Gisler RH, Imhof BA, Preissner KT. Urokinase receptor (CD87) regulates leukocyte recruitment via beta 2 integrins in vivo. J Exp Med 1998; 188: 1029-1037.
64. Gyetko MR, Sud S, Kendall T, Fuller JA, Newstead MW, Standiford TJ. Urokinase receptor-deficient mice have impaired neutrophil recruitment in response to pulmonary Pseudomonas aeruginosa infection. J Immunol 2000; 165: 1513-1519.
65. Gyetko MR, Aizenberg D, Mayo-Bond L., Pu J. Urokinasedeficient and urokinase receptor-deficient mice have impaired neutrophil antimicrobial activation in vitro. Leukoc Biol 2004; 76: 648-656.
66. D'mello V, Singh S, Wu Y, Birge RB. The urokinase plasminogen activator receptor promotes efferocytosis of apoptotic cells. J Biol Chem 2009; 284: 17030-17038.
67. Park Y-J, Liu G, Tsuruta Y, Lorne E, Abraham E. Participation of the urokinase receptor in neutrophil efferocytosis. Blood 2009; 114: 860-870.
68. Fevang B, Eugen-Olsen J, Yndestad A, et al. Enhanced levels of urokinase plasminogen activator and its soluble receptor in common variable immunodeficiency. Clin Immunol 2009; 131: 438-446.
69. Kitching AR, Holdsworth SR, Ploplis VA, et al. Plasminogen and plasminogen activators protect against renal injury in crescentis glomerulonephritis. J Exp Med 1997; 185: 963-968.
70. Wei C, Möller CC, Altintas MM, Li J, et al. Modification of kidney barrier function by the urokinase receptor. Nat Med 2008; 14: 55-63.
71. Nagai N, Okada K, Kawao N, et al. Urokinase-type plasminogen activator receptor (uPAR) augments brain damage in a murine model of ischemic stroke. Neurosci Lett 2008; 432: 46-49.
72. Heymans S, Pauschinger M, De Palma A, et al. Inhibition of urokinase-type plasminogen activator or matrix metalloproteinases prevents cardiac injury and dysfunction during viral myocarditis. Circulation 2006; 114: 2565-2573.
73. Falkenberg M, Tom C, DeYoung MB, Wen S, Linnemann R, Dichek DA. Increased expression of urokinase during atherosclerotic lesion development causes arterial constriction and lumen loss, and accelerates lesion growth. Proc Natl Acad Sci USA 2002; 99: 10665-10670.
74. Rossignol P, Luttun A, Martin-Ventura JL, et al. Plasminogen activation: a mediator of vascular smooth muscle cell apoptosis in atherosclerotic plaques. J Thromb Haemost 2006; 4: 664-670.
75. Svensson PA, Olson FJ, Hägg DA, et al. Urokinase-type plasminogen activator receptor is associated with macrophages and plaque rupture in symptomatic carotid atherosclerosis. Int J Mol Med 2008; 22: 459-464.
76. Vallabhaneni KC, Tkachuk S, Kiyan Y, et al. Urokinase receptor mediates mobilization, migration and differentiation of mesenchymal stem cells. Cardiovasc Res 2010; 90:113-121.
77. Suelves M, Vidal B, Serrano AL, Tjwa M, et al. UPA deficiency exacerbates muscular dystrophy in MDX mice. J Cell Biol 2007; 178:1039-1051.
78. Zhou HM, Nichols A, Meda P, Vassalli JD. Urokinase-type plasminogen activator and its receptor synergize to promote pathogenicproteolysis. EMBO J 2000; 19: 4817-4826.
79. Selleri C, Montuori N, Ricci P, et al. Involvement of the urokinasetype plasminogen activator receptor in hematopoietic stem cell mobilization. Blood 2005; 105: 2198-2205.
80. Selleri C, Montuori N, Ricci P, et al. In vivo activity of the cleaved form of soluble urokinase receptor: a new hematopoietic stem/progenitor cell mobilizer. Cancer Res 2006; 66: 10885-10890.
81. Furlan F, Galbiati C, Jorgensen NR, et al. Role of urokinase plasminogen activator receptor in bone homeostasis. J Bone Min Res 2007; 22: 1387-1396.
82. Tjwa M, Sidenius N, Moura R, et al. Membrane-anchored uPAR regulates the proliferation, marrow pool size, engraftment, and mobilization of mouse hematopoietic stem/progenitor cells. J Clin Invest 2009; 119: 1008-18.
83. Riccio A, Grimaldi G, Verde P, Sebastio G, Boast S, Blasi F. The human urokinase-plasminogen activator gene and its promoter. Nucleic Acids Res 1985; 13: 2759-27571.
84. Ferrai C, Munari D, Luraghi P, et al. A transcription-dependent micrococcal nuclease-resistant fragment of the urokinase-type plasminogen activator promoter interacts with the enhancer. J Biol Chem 2007; 282: 12537-12546.
85. rigoyen JP, Munoz-Canoves P, Montero L, Koziczak M, Nagamine Y. The plasminogen activator system: biology and regulation. Cell Mol Life Sci 1999; 56: 104-132.
86. Shimizu M, Cohen B, Goldvasser P, et al. Plasminogen activator uPA is a direct transcriptional target of the JAG1-Notch receptor signaling pathway in breast cancer. Cancer Res 2011; 71: 277-286.
87. Belaguli NS, Aftab M, Rigi M, Zhang M, Albo D, Berger DH. GATA6 promotes colon cancer cell invasion by regulating urokinase plasminogen activator gene expression. Neoplasia 2010; 12: 856-865.
88. Tran H, Schilling M, Wirbelauer C, Hess D, Nagamine Y. Facilitation of mRNA deadenylation and decay by the exosomebound, DExH protein RHAU. Mol Cell 2004; 13:101-111.
89. Chalupníková K, Lattmann S, Selak N, Iwamoto F, Fujiki Y, Nagamine Y.J. Recruitment of the RNA helicase RHAU to stress granules via a unique RNA-binding domain. Biol Chem 2008; 283: 35186-35198.
90. Al-Souhibani N, Al-Ahmadi W, Hesketh JE, Blackshear PJ, Khabar KS. The RNA-binding zinc-finger protein tristetraprolin regulates AU-rich mRNAs involved in breast cancer-related processes. Oncogene 2010; 29: 4205-42015.
91. Shiou SR, Datta PK, Dhawan P, et al. Smad4-dependent regulation of urokinase plasminogen activator secretion and RNA stability associated with invasiveness by autocrine and paracrine transforming growth factor-beta. J Biol Chem 2006; 281: 33971-33981.
92. Salvi A, Sabelli C, Moncini S, et al. MicroRNA-23b mediates urokinase and c-met downmodulation and a decreased migration of human hepatocellular carcinoma cells. FEBS J 2009; 276: 2966-2982.
93. Li XF, Yan PJ, Shao ZM. Downregulation of miR-193b contributes to enhance (uPA) expression and tumor progression and invasion in human breast cancer. Oncogene 2009; 28: 3937-3948.
94. List K, Jensen ON, Bugge TH, Lund LR, Ploug M, Dano K, Behrendt N. Plasminogen-independent initiation of the pro-urokinase activation cascade in vivo. Activation of pro-urokinase by glandular kallikrein (mGK-6) in plasminogen-deficient mice. Biochemistry 2000; 39: 508-515.
95. Buko AM, Kentzer EJ, Petros A, Menon G, Zuiderweg ER, Sarin VK. Characterization of a posttranslational fucosylation in the growth factor domain of urinary plasminogen activator. Proc Natl Acad Sci USA 1991; 88: 3992-3996.
96. Franco P, Mastronicola MR, De Cesare D, et al. Separation and characterization of nonphosphorylated and serine-phosphorylated urokinase. Catalytic properties and sensitivity to plasminogen activatorinhibitor type 1. J Biol Chem 1992; 267: 19369-19372.
97. Franco P, Iaccarino C, Chiaradonna F, et al. Phosphorylation of pro-urokinase at Ser138/303 impairs its receptor-dependent ability to promote myelomonocytic adhesion and motility. J Cell Biol 1997; 137: 779-791.
98. Novokhatny V, Medved L, Mazar A, Marcotte P, Henkin J, Ingham K. Domain structure and interactions of recombinant urokinasetype plasminogen activator. J Biol Chem 1992; 267: 3878-3885.
99. Lavorgna G, Patthy L, Boncinelli E. Were protein internal repeats formed by bricolage? Trends Genet 2001; 17: 120-123.
100. Nagata K, Kohda D, Hatanaka H, et al. Solution structure of the epidermal growth factor-like domain of heregulin-alpha, a ligand for p180erbB-4. EMBO J 1994; 13: 3517-3523.
101. Patthy L. Evolution of the proteases of blood coagulation and fibrinolysis by assembly from modules. Cell 1985; 41: 657-663.
102. Li X, Bokman AM, Llinàs M, Smith RA, Dobson CM. Solution structure of the kringle domain from urokinase-type plasminogen activator. J Mol Biol 1994; 235: 1548-1559.
103. Liu M, Zhang S. A kringle-containing protease with plasminogenlike activity in the basal chordate Branchiostoma belcheri. Biosci Rep 2009; 29: 385-395.
104. Stephens RW, Bokman AM, Myöhänen HT, et al. Heparin binding to the urokinase kringle domain. Biochemistry 1992; 31: 7572-7579.
105. Barinka C, Parry G, Callahan J, et al. Structural basis of interaction between urokinase-type plasminogen activator and its receptor. J Mol Biol 2006; 363: 482-495.
106. van der Voort R, Taher TE, Derksen PW, Spaargaren M, van der Neut R, Pals ST. The hepatocyte growth factor/Met pathway in development, tumourigenesis, and B-cell differentiation. Adv Cancer Res 2000; 79: 39-90.
107. Resnati M, Guttinger M, Valcamonica S, Sidenius S, Blasi F, Fazioli F. Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect. EMBO J 1996; 15: 1572-1582.
108. Gargiulo L, Longanesi-Cattani I, Bifulco K, et al. Cross-talk between fMLF and vitronectin receptors triggered by urokinase receptor-derived SRSRY peptide. J Biol Chem 2005; 280: 25225-25232.
109. Ellis V, Behrendt N, Dano K. Plasminogen activation by receptorbound urokinase. A kinetic study with both cell-associated and isolated receptor. J Biol Chem 1991; 266: 12752-1278.
110. Gong Y, Hart E, Shchurin A, Hoover-Plow J. Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice. J Clin Invest 2008; 118: 3012-3024.
111. Carmeliet P, Moons L, Lijnen R, et al. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet 1997; 17: 439-444.
112. Rømer MU, Kirkebjerg DA, Knud Larsen J, et al. Indication of a role of plasminogen activator inhibitor type I in protecting murine fibrosarcoma cells against apoptosis. Thromb Haemost 2005; 94: 859-866.
113. Romer J, Bugge TH, Pyke C, Lund LR, Flick MJ, Degen JL, Dano K. Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med 1996; 2: 287-292.
114. Appella E, Robinson EA, Ullrich, SJ, et al. The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. J Biol Chem 1985; 262: 4437-4440.
115. Magdolen V, Rettenberger P, Koppitz M, et al. Systematic mutational analysis of the receptor-binding region of the human urokinase-type plasminogen activator. Eur J Biochem 1996; 237: 743-751.
116. Huai Q, Mazar AP, Kuo A, et al. Structure of human urokinase plasminogen activator in complex with its receptor. Science 2006; 311: 656-659.
117. Lin L, Gårdsvoll H, Huai Q, Huang M, Ploug M. Structure-based engineering of species selectivity in the interaction between urokinase and its receptor: implication for preclinical cancer therapy. J Biol Chem 2010; 285: 10982-10992.
118. Bdeir K, Kuo A, Sachais BS, et al. The kringle stabilizes urokinase binding to the urokinase receptor. Blood 2003; 102: 3600-3608.
119. Connolly BM, Choi EY, Gårdsvoll H, et al. Selective abrogation of the uPA-uPAR interaction in vivo reveals a novel role in suppression of fibrin-associated inflammation. Blood 2010; 116: 1593-1603.
120. Henneke I, Greschus S, Savai R, et al. Inhibition of urokinase activityreduces primary tumour growth and metastasis formation in a murine lung carcinoma model. Am J Respir Crit Care Med 2010; 18: 611-619.
121. Alfano D, Franco P, Vocca I, et al. The urokinase plasminogen activator and its receptor: role in cell growth and apoptosis. Thromb Haemost 2005; 93: 205-211.
122. Kim KS, Hong YK, Joe YA, et al. Anti-angiogenic activity of the recombinant kringle domain of urokinase and its specific entry into endothelial cells. J Biol Chem 2003; 278: 11449-1151.
123. Mukhina S, Stepanova V, Traktouev D, et al. The chemotactic action of urokinase on smooth muscle cells is dependent on its kringle domain. Characterization of interactions and contribution to chemotaxis. J Biol Chem 2000; 275: 16450-16458.
124. Franco P, Massa, O, Garcia-Rocha M, Chiaradonna F, et al. Protein kinase C-dependent in vivo phosphorylation of prourokinase leads to the formation of a receptor competitive antagonist. J Biol Chem 1998; 273: 27734-27740.
125. Guo Y, Higazi AA, Arakelian A, et al. Peptide derived from the non receptor binding region of urokinase plasminogen activator (uPA) inhibits tumour progression and angiogenesis and induces tumour cell death in vivo. FASEB J 2000; 14: 1400-1410.
126. Borglum AD, Byskov A, Ragno P, et al. Assignment of the urokinase-type plasminogen activator receptor gene (PLAUR) to chromosome 19q13.1-q13.2. Am J Hum Genet 1992; 50: 492-497.
127. Casey JR, Petranka JG, Kottra J, Fleenor DE, Rosse WF. The structure of the urokinase-type plasminogen activator receptor gene. Blood 1994; 84: 1151-1156.
128. Roldan AL, Cubellis MV, Masucci MT, et al. Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin dependent proteolysis. EMBO J 1990; 9: 467-474.
129. Soravia E, Grebe A, De Luca P, et al. A conserved TATA-less proximal promoter drives basal transcription from the urokinasetype plasminogen activator receptor gene. Blood 1995; 86: 624-35.
130. Allgayer H, Wang H, Gallick GE, et al. Transcriptional induction of the urokinase receptor gene by a constitutively active Src. Requirement of an upstream motif (-152/-135) bound with Sp1. J Biol Chem 1999; 274: 18428-184237.
131. Zannetti A, Del Vecchio S, Carriero MV, et al. Coordinate upregulation of Sp1 DNA-binding activity and urokinase receptor expression in breast carcinoma. Cancer Res 2000; 60: 1546-1551.
132. Silvestri I, Longanesi Cattani I, Franco P, et al. Engaged urokinase receptors enhance tumor breast cell migration and invasion by upregulating alpha(v)beta5 vitronectin receptor cell surface expression. Int J Cancer 2002; 102: 562-571
133. Trisciuoglio D, Iervolino A, Candiloro A, et al. Bcl-2 induction of urokinase plasminogen activator receptor expression in human cancer cells through Sp1 activation: involvement of ERK1/ERK2 activity. J Biol Chem 2004; 279: 6737-6745.
134. Büchler P, Reber HA, Tomlinson JS, et al. Transcriptional regulation of urokinase-type plasminogen activator receptor by hypoxiainducible factor 1 is crucial for invasion of pancreatic and liver cancer. Neoplasia 2009; 11: 196-206.
135. Stewart CE, Sayers I. Characterisation of urokinase plasminogen activator receptor variants in human airway and peripheral cells. BMC Mol Biol 2009 10:75.
136. Sato S, Kopitz C, Grismayer B, et al. Overexpression of the urokinase receptor mRNA splice variant uPAR-del4/5 affects tumor- associated processes of breast cancer cells in vitro and in vivo. Breast Cancer Res Treat 2010; Jul 16.
137. Shetty S, Velusamy T, Idell S, et al. Regulation of urokinase receptor expression by p53: novel role in stabilization of uPAR mRNA. Mol Cell Biol 2007; 27: 5607-5618.
138. Velusamy T, Shetty P, Bhandary YP, Liu MC, Shetty S. Posttranscriptional regulation of urokinase receptor expression by heterogeneous nuclear ribonuclear protein C. Biochemistry 2008; 47: 6508-6517.
139. Sasayama T, Nishihara M, Kondoh T, Hosoda K, Kohmura E. MicroRNA-10b is overexpressed in malignant glioma and associated with tumor invasive factors, uPAR and RhoC. Int J Cancer 2009; 125: 1407-1413.
140. Stoppelli MP, Corti A, Soffientini A, Cassani G, Blasi F, Assoian RK. Differentiation-enhanced binding of the amino-terminal fragment of human urokinase plasminogen activator to a specific receptor on U937 monocytes. Proc Natl Acad Sci USA 1985; 82: 4939-4943.
141. Vassalli JD, Baccino D, Belin D. A cellular binding site for the Mr55,000 form of the human plasminogen activator, urokinase. J Cell Biol 1985; 100: 86-92.
142. Nielsen LS, Kellerman GM, Behrendt N, Picone R, Danø K, Blasi F. A 55,000-60,000 Mr receptor protein for urokinase-type plasminogen activator. Identification in human tumor cell lines and partial purification. J Biol Chem 1988; 263: 2358-2363.
143. Estreicher A, Wohlwend A, Belin D, et al. Characterization of the cellular binding site for the urokinase-type plasminogen activator. J Biol Chem 1989; 264: 1180-1189.
144. Møller LB, Ploug M, Blasi F. Structural requirements for glycosylphosphatidylinositol- anchor attachment in the cellular receptor for urokinase plasminogen activator. Eur J Biochem 1992; 208: 493-500.
145. Behrendt N, Rønne E, Ploug M, et al. The human receptor for urokinase plasminogen activator. NH2-terminal amino acid sequence and glycosylation variants. J Biol Chem 1990; 265: 6453-6460.
146. 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 1993; 268: 17539-175346.
147. 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 venom alpha- neurotoxins. FEBS Lett 1994; 349: 163-168.
148. Llinas P, Le Du MH, Gårdsvoll H, et al. Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide. EMBO J 2005; 24:1655-1663.
149. Klein DE, Stayrook SE, Shi F, Narayan K, Lemmon MA. Structural basis for EGFR ligand sequestration by Argos. Nature 2008; 453: 1271-1275.
150. Carriero MV, Del Vecchio S, Franco P, et al. Vitronectin binding to urokinase receptor in human breast cancer. Clin Cancer Res 1997; 3: 1299-1308.
151. Carriero MV, Del Vecchio S, Capozzoli M, et al. Urokinase receptor interacts with alpha(v)beta5 vitronectin receptor, promoting urokinase-dependent cell migration in breast cancer. Cancer Res 1999; 59:5307-5314.
152. Huai Q, Zhou A, Lin L, et al. Crystal structures of two human Vn, urokinase and urokinase receptor complexes. Nat Struct Mol Biol 2008; 15, 422-423.
153. Madsen CD, Ferraris GM, Andolfo A, Cunningham O, Sidenius N. UPAR-induced cell adhesion and migration: vitronectin provides the key. J Cell Biol 2007; 177: 927-939.
154. Gårdsvoll H, Ploug M. Mapping of the vitronectin-binding site on the urokinase receptor: involvement of a coherent receptor interface consisting of residues from both domain I and the flanking interdomain linker region. J Biol Chem 2007; 282: 13561-1372.
155. Kjaergaard, M., Hansen, L.V., Jacobsen, B., Gardsvoll, H. and Ploug, M. Structure and ligand interactions of the urokinase receptor (uPAR). Front.Biosci 2008; 13: 5441-5461.
156. Sidenius N, Andolfo A, Fesce R, Blasi F. Urokinase regulates Vn binding by controlling urokinase receptor oligomerization. J Biol Chem 2002; 277: 27982-27990.
157. Caiolfa VR, Zamai M, Malengo G, et al. Monomer dimer dynamics and distribution of GPI-anchored uPAR are determined by cell surface protein assemblies. J Cell Biol 2007; 179: 1067-1082.
158. Malengo G, Andolfo A, Sidenius N, Gratton E, Zamai M, Caiolfa VR. Fluorescence correlation spectroscopy and photon counting histogram on membrane proteins: functional dynamics of the glycosylphosphatidylinositol-anchored urokinase plasminogen activator receptor. J Biomed Opt 2008; 13: 031215.
159. Sidenius N, Blasi F. Domain 1 of the urokinase receptor (uPAR) is required for uPAR-mediated cell binding to vitronectin. FEBS Lett 2000; 470: 40-46.
160. 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 2001; 20: 2032-2003.
161. 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 1997;16:7279-7286.
162. Trigwell S, Wood L, Jones P. Soluble urokinase receptor promotes cell adhesion and requires tyrosine-92 for activation of p56/59(hck). Biochem Biophys Res Commun 2000; 278: 440-446.
163. Montuori N, Carriero MV, Salzano S, Rossi G, Ragno P. The cleavage of the urokinase receptor regulates its multiple functions. J Biol Chem 2002; 277: 46932-46939.
164. de Paulis A, Montuori N, Prevete N, et al. Urokinase induces basophil chemotaxis through a urokinase receptor epitope that is an endogenous ligand for formyl peptide receptor-like 1 and -like 2. J Immunol 2004;173: 5739-5748.
165. Furlan F, Orlando S, Laudanna C, et al. The soluble D2D3(88-274) fragment of the urokinase receptor inhibits monocyte chemotaxis and integrin-dependent cell adhesion. J Cell Sci 2004; 117: 2909-2916.
166. Degryse B, Resnati M, Czekay RP, Loskutoff DJ, Blasi F. Domain 2 of the urokinase receptor contains an integrin-interacting epitope with intrinsic signaling activity: generation of a new integrin inhibitor. J Biol Chem 2005; 280: 24792-24803.
167. Høyer-Hansen G, Rønne E, Solberg H, et al. Urokinase plasminogen activator cleaves its cell surface receptor releasing the ligandbinding domain. J Biol Chem 1992; 267: 18224-18229.
168. Wilhelm OG, Wilhelm S, Escott GM, et al. Cellular glycosylphosphatidylinositol- specific phospholipase D regulates urokinase receptor shedding and cell surface expression. J Cell Physiol 1999; 180:225-235.
169. Kruger A, Soeltl R, Lutz V, et al. Reduction of breast carcinoma tumor growth and lung colonization by overexpression of the soluble urokinase-type plasminogen activator receptor (CD87). Cancer Gene Ther 2000; 7: 292-299.
170. Lutz V, Reuning U, Krüger A, et al. High level synthesis of recombinant soluble urokinase receptor (CD87) by ovarian cancer cells reduces intraperitoneal tumor growth and spread in nude mice. Biol Chem 2001; 382: 789-798.
171. Margheri F, Manetti M, Serratì S, et al. Domain 1 of the urokinasetype plasminogen activator receptor is required for its morphologic and functional, beta2 integrin-mediated connection with actin cytoskeleton in human microvascular endothelial cells: failure of association in systemic sclerosis endothelial cells. Arthritis Rheum 2006; 54: 3926-3938.
172. Blasi F, Carmeliet P. uPAR: a versatile signaling orchestrator. Nat Rev Mol Cell Biol 2002; 3: 932-943.
173. Smith HW, Marshall CJ. Regulation of cell signaling by uPAR. Nat Rev Mol Cell Biol 2010; 11: 23-36.
174. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010; 10: 9-22.
175. Bohuslav J, Horejsí V, Hansmann C, et al. Urokinase plasminogen activator receptor, beta 2-integrins, and Src-kinases within a single receptor complex of human monocytes. J Exp Med 1995; 181:1381-13890.
176. Dumler I, Weis A, Mayboroda OA, et al. The Jak/Stat pathway and urokinase receptor signaling in human aortic vascular smooth muscle cells. J Biol Chem 1998; 273: 315-321.
177. Goodson RJ, Doyle MV, Kaufman SE, Rosenberg S. High-affinityurokinase receptor antagonists identified with bacteriophage peptide display. Proc Natl Acad Sci USA 1994; 9: 7129-7133.
178. Zhang F, Tom CC, Kugler MC, et al. Distinct ligand binding sites in integrin alpha3beta1 regulate matrix adhesion and cell-cell contact. J Cell Biol 2003; 163: 177-188.
179. Xue W, Mizukami I, Todd RF 3rd, Petty HR. Urokinase-type plasminogen activator receptors associate with beta1 and beta3 integrins of fibrosarcoma cells: dependence on extracellular matrix components. Cancer Res 1997; 57:1682-1689.
180. 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 1999; 147: 89-104.
181. Wei Y, Czekay RP, Robillard L, Kugler MC, et al. Regulation of alpha5beta1 integrin conformation and function by urokinase receptor binding. J Cell Biol 2005; 168: 501-511.
182. Wei Y, Yang X, Liu Q, Wilkins JA, Chapman HA. A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling. J Cell Biol 1999; 144: 1285-1294.
183. Monaghan-Benson E, Mastick CC, McKeown-Longo PJ. A dual role for caveolin-1 in the regulation of fibronectin matrix assembly by uPAR. J Cell Sc 2008; 121: 3693-3703.
184. Chaurasia P, Mezei M, Zhou MM, Ossowski L. Computer aided identification of small molecules disrupting uPAR/alpha5beta1-integrin interaction: a new paradigm for metastasis prevention. PLoS One 2009; 4: e4617.
185. Wei Y, Tang CH, Kim Y, Robillard L, et al. Urokinase receptors are required for alpha 5 beta 1 integrin-mediated signaling in tumor cells. J Biol Chem 2007; 282: 3929-3939.
186. Xia Y, Borland G, Huang J, et al. Function of the lectin domain of Mac-1/complement receptor type 3 (CD11b/ CD18) in regulating neutrophil adhesion. J Immunol 2002; 169: 6417-6426.
187. Xiong JP, Stehle T, Diefenbach B, et al. Crystal structure of the extracellular segment of integrin alphavbeta3. Science 2001; 294: 339-345.
188. Gavins FR. Are formyl peptide receptors novel targets for therapeutic intervention in ischaemia-reperfusion injury? Trends in Pharmacological Sciences 2010; 31: 266-276.
189. Rabiet MJ, Huet E, Boulay F. The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview. Biochimie 2007; 89: 1089-1106.
190. Bae YS, Song JY, Kim Y, et al. Differential activation of formyl peptide receptor signaling by peptide ligands. Mol Pharmacol 2003; 64: 841-847.
191. de Paulis A, Florio G, Prevete N, et al. HIV-1 envelope gp41 peptides promote migration of human Fc epsilon RI+ cells and inhibit IL-13 synthesis through interaction with formyl peptide receptors. J Immunol 2002; 169: 4559-4567.
192. Le Y, Yang Y, Cui Y, Yazawa H, Gong W, Qiu C, Wang JM. Receptors for chemotactic formyl peptides as pharmacological targets. Int Immunopharmacol 2002; 2: 1-13.
193. Rescher U, Danielczyk A, Markoff A, Gerke V. Functional activation of the formyl peptide receptor by a new endogenous ligand in human lung A549 cells. J Immunol 2002; 169: 1500-1504.
194. McCoy R, Haviland DL, Molmenti EP, Ziambaras T, Wetsel RA, Perlmutter DH N-formylpeptide and complement C5a receptors are expressed in liver cells and mediate hepatic acute phase gene regulation. J Exp Med 1995;182: 207-217.
195. Kim MK, Min do S, Park YJ, Kim JH, Ryu SH, Bae YS. Expression and functional role of formyl peptide receptor in human bone marrow-derived mesenchymal stem cells. FEBS Lett. 2007; 581: 1917-1922.
196. Huang J, Chen K, Chen J, et al. The G-protein-coupled formylpeptide receptor FPR confers a more invasive phenotype on human glioblastoma cells. Br J Cancer 2010; 102: 1052-1060.
197. Montuori N, Bifulco K, Carriero MV, et al. The cross-talk between the urokinase receptor and fMLP receptors regulates the activity of the CXCR4 chemokine receptor. Cell Mol Life Sci 2010; Oct 24.
198. Jo M, Thomas KS, Marozkina N, Amin TJ, Silva CM, Parsons SJ, Gonias SL. Dynamic assembly of the urokinase-type plasminogen activator signaling receptor complex determines the mitogenic activity of urokinase-type plasminogen activator. J Biol Chem 2005; 280: 17449-17457.
199. Liu D, Aguirre Ghiso J, 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 2002; 1: 445-457.
200. D'Alessio S, Gerasi L, and Blasi F. The urokinase receptor (uPAR) Ko mice keratinocytes fail to produce EGF-receptor-dependent Laminin-5 affecting migration in vitro and in vivo. J Cell Sci 2008; 121: 3922-3932.
201. Kiyan J, Kiyan R, Haller H, Dumler I. Urokinase-induced signaling in human vascular smooth muscle cells is mediated by PDGFRbeta. EMBO J 2005; 24: 1787-1797.
202. Collen D, Lijnen HR Thrombolytic agents. Thromb Haemost 2005; 93: 627-630.
203. Longstaff C. Studies on the mechanisms of action of aprotinin and tranexamic acid as plasmin inhibitors and antifibrinolytic agents. Blood Coagul Fibrinolysis 1994; 5: 537-542.
204. Ke SH, Coombs GS, Tachias K, Corey DR, Madison EL. Optimal subsite occupancy and design of a selective inhibitor of urokinase. J Biol Chem 1997; 272: 20456-20462.
205. Zeslawska E, Schweinitz A, Karcher A, et al. Crystals of the urokinase type plasminogen activator variant beta(c)-uPAin complex with small molecule inhibitors open the way towards structure-based drug design. J Mol Biol 2000; 301: 465-475.
206. Schweinitz A, Steinmetzer T, Banke IJ, et al. Design of novel and selective inhibitors of urokinase-type plasminogen activator with improved pharmacokinetic properties for use as antimetastatic agents. J Biol Chem 2004; 279: 33613-33622.
207. Setyono-Han B, Sturzebecher J, Schmalix WA, et al. Suppression of rat breast cancer metastasis and reduction of primary tumour growth by the small synthetic urokinase inhibitor wx-uk1. Thromb Haemost 2005; 93: 779-786.
208. Zhu M, Gokhale VM, Szabo L, et al. Identification of a novel inhibitor of urokinase-type plasminogen activator. Mol Cancer Ther 2007; 6: 1348-1356.
209. Heinemann V, Ebert MP, Pinter T, Bevan P, Neville NG, Mala C. Randomized phase II trial with an uPA inhibitor (WX-671) in patients with locally advanced nonmetastatic pancreatic cancer). ASCO Annual Meeting Proceedings (Post-Meeting Edition) J Clin Onc 2010; 28: 4060.
210. Hansen M, Wind T, Blouse GE, et al. A urokinase-type plasminogen activator-inhibiting cyclic peptide with an unusual P2 residue and an extended protease binding surface demonstrates new modalities for enzyme inhibition. J Biol Chem 2005; 280: 38424-3837.
211. Zhao G, Yuan C, Wind T, Huang Z, Andreasen PA, Huang M. Structural basis of specificity of a peptidyl urokinase inhibitor, upain-1. J Struct Biol 2007; 160: 1-10.
212. Andersen LM, Wind T, Hansen HD, Andreasen PA. A cyclic peptidylic inhibitor of murine urokinase-type plasminogen activator: Changing species specificity by substitution of a single residue. Biochem J 2008; 412: 447-457.
213. Liu S, Bugge TH, Leppla SH. Targeting of tumor cells by cell surface urokinase plasminogen activator-depend activated selectively on the surface of uPAR-expressing tumor cells in the presence of pro-uPA and Plg ent anthrax toxin. J Biol Chem 2001; 276:17976-17984.
214. Su Y, Ortiz J, Liu S, Bugge TH, et al. Systematic urokinaseactivated anthrax toxin therapy produces regressions of subcutaneous human non-small cell lung tumour in athymic nude mice. Cancer Res 2007; 67: 3329-3336.
215. Barnathan ES, Kuo A, Rosenfeld L, et al. Interaction of singlechainurokinase-type plasminogen activator with human endothelial cells. J Biol Chem 1990; 265: 2865-2872.
216. 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 1997; 172: 137-45.
217. 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 1996; 56: 2428-2433.
218. 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 factor-like domain of urokinase in the experimentaland spontaneous metastasis model. Int J Cancer 1994; 57: 727-733.
219. Magdolen V, Bürgle M, de Prada NA, et al. Cyclo19,31[D-Cys19]- uPA19-31 is a potent competitive antagonist of the interaction of urokinase-type plasminogen activator with its receptor (CD87). BiolChem 2001; 382: 1197-1205.
220. Schmiedeberg N, Schmitt M, Rolz C, et al. Synthesis, solution structure, and biological evaluation of urokinase type plasminogen activator (uPA)-derived receptor binding domain mimetics. J Med Chem 2002; 45: 4984-4994.
221. Sato S, Kopitz C, Schmalix WA, et al. High-affinity urokinasederived cyclic peptides inhibiting urokinase/urokinase receptorinteraction: effects on tumor growth and spread. FEBS Lett 2002; 528: 212-216.
222. Ploug M, Østergaard S, Gårdsvoll H, 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 2001; 40: 12157-12168.
223. Piironen T, Laursen B, Pass J, et al., Specific immunoassays for detection of intact and cleaved forms of the urokinase receptor. Clin Chem 2004; 50: 2059-2068.
224. Duriseti S, Goetz DH, Hostetter DR, LeBeau AM, Wei Y, Craik CS. Antagonistic anti-urokinase plasminogen activator receptor (uPAR) antibodies significantly inhibit uPAR-mediated cellular signaling and migration. J Biol Chem 2010; 285: 26878-26888.
225. Fabbrini MS, Rappocciolo E, Carpani D, et al. Characterization of a saporin isoform with lower ribosome-inhibiting activity. Biochem J 1997; 322:719-727.
226. Kim CK, Hong SH, Joe YA, Shim BS, Lee SK, Hong YK. The recombinant kringle domain of urokinase plasminogen activator inhibits in vivo malignant glioma growth. Cancer Sci 2007; 98: 253-258.
227. Kim CK, Joe YA, Lee SK, et al. Enhancement of anti-tumour activity by low-dose combination of the recombinant urokinase kringle domain and celecoxib in a glioma model. Cancer Lett 2010; 288: 251-260.
228. Chung AS, Lee J, Ferrara N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nature Reviews Cancer 2010; 10: 505-514.
229. Carriero MV, Franco P, Gargiulo L, et al. Inhibition of receptordependent urokinase signaling by specific Ser to Glu substitutions. Biol Chem 2002; 383:107-113.
230. Vocca I, Franco P, Alfano D, et al. Inhibition of migration and invasion of carcinoma cells by urokinase-derived antagonists of alphavbeta5 integrin activation. Int J Cancer 2009; 124: 316-325.
231. Guo Y, Mazar AP, Lebrun J, Rabbani SA. An antiangiogenic urokinase derived peptide combined with tamoxifen decreases tumour growth and metastasis in a syngeneic model of breast cancer. Cancer Res 2002; 62: 4678-4684.
232. Mishima K, Mazar AP, Gown A, et al. A peptide derived from the non-receptor-binding region of urokinase plasminogen activator inhibits glioblastoma growth and angiogenesis in vivo in combination with cisplatin. Proc Natl Acad Sci USA 2000; 97: 8484-8489.
233. McGuire PG, Jones TR, Talarico N, Warren E, Das A. The urokinase/urokinase receptor system in retinal neovascularization: inhibition by A6 suggests a new therapeutic target. Invest Ophthalmol Vis Sci 2003; 44: 2736-2742.
234. Navaratna D, Menicucci G, Maestas J, Srinivasan R, McGuire P, Das AA. Peptide inhibitor of the urokinase/urokinase receptor system inhibits alteration of the bloodretinal barrier in diabetes. FASEB J 2008; 22: 3310-337.
235. Berkenblit A, Matulonis UA, Kroener JF, et al. A6, an urokinase plasminogen activator (uPA)-derived peptide in patients with advanced gynecologic cancer: a phase I trial. Gynecol Oncol 2005; 99: 50-57.
236. Ghamande SA, Silverman MH, Huh W, et al. A phase 2, randomized, double-blind, placebo-controlled trial of clinical activity and safety of subcutaneous A6 in women with asymptomatic CA125 progression after first-line chemotherapy of epithelial ovarian cancer. Gynecol Oncol 2008; 111: 89-94.
237. Bifulco K, Longanesi-Cattani I, Gargiulo L, et al. An urokinase receptor antagonist that inhibits cell migration by blocking the formyl peptide receptor. FEBS Lett 2008; 582: 1141-1146.
238. Carriero MV, Longanesi-Cattani I, Bifulco K, et al. Structure-based design of an urokinase-type plasminogen activator receptor-derived peptide inhibiting cell migration and lung metastasis. Mol Cancer Ther 2009; 9: 2708-2717.
239. Resnati M, Pallavicini I, Daverio R, Sidenius N, Bonini P, Blasi F. Specific immunofluorimetric assay detecting the chemotactic epitope of the urokinase receptor (uPAR). J Immunol Methods 2006; 308: 192-202.
240. Ahmed N, Oliva K, Wang Y, Quinn M, Rice G. Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR-beta1 integrin complex in colon cancer cells. Br J Cancer 2003; 89: 374-384.
241. van der Pluijm G, Sijmons B, Vloedgraven H, et al. Urokinasereceptor/ integrin complexes are functionally involved in adhesion and progression of human breast cancer in vivo. Am J Pathol 2001; 159: 971-982.
242. Simon DI, Wei Y, Zhang L, et al. Identification of a urokinase receptor- integrin interaction site. Promiscuous regulator of integrin function. J Biol Chem 2000; 275: 10228-10234.
243. Ghosh S, Johnson JJ, Sen R, et al. Functional relevance of urinarytype plasminogen activator receptor-alpha3beta1 integrin association in proteinase regulatory pathways. J Biol Chem 2006; 281: 13021-13029.
244. Chaurasia P, Aguirre-Ghiso JA, Liang OD, Gardsvoll H, Ploug M, Ossowski L. A region in urokinase plasminogen receptor domain III controlling a functional association with alpha5beta1 integrinand tumor growth. J Biol Chem 2006; 28:1 4852-4863.
245. Kenny HA, Leonhardt P, Ladanyi A, Montag A, Im HK, Jagadeeswaran S, Shaw DE, Mazar AP, Lengyel E., et al. Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis. Clin Cancer Res 2011; 17: 459-471.
246. Rasheed SA, Efferth T, Asangani IA, Allgayer HI. First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases. Int J Cancer 2010; 127: 1475-1485.
247. Jiang M, Bujo H, Zhu Y, et al. Pitavastatin attenuates the PDGFinduced LR11/uPA receptor-mediated migration of smooth muscle cells. Biochem Biophys Res Commun 2006; 348: 1367-1377.
248. Nikolova DA, Asangani IA, Nelson LD, et al. Cetuximab attenuates metastasis and uPAR expression in non-small cell lung cancer: u-PAR and E-cadherin are novel biomarkers of cetuximab sensitivity. Cancer Res 2009; 69: 2461-2470.
249. Koster A, Schirmer U. Re-evaluation of the role of antifibrinolytic therapy with lysine analogs during cardiac surgery in the post aprotinin era. Curr Opin Anaesthesiol 2011; 24: 92-97.