uPAR – uPA – PAI-1 interactions and signaling: A vascular biologist’s view

Summary

The urokinase-type plasminogen activator (uPA), its inhibitor PA I-1 and its cellular receptor (uPAR), play a pivotal role in pericellular proteolysis. In addition, through their interactions with extracellular matrix proteins as well as with transmembrane receptors and other links to the intracellular signaling machinery, they modulate cell migration, cell-matrix interactions and signaling pathways. A large body of experimental evidence from in-vitro and in-vivo data as well as from the clinics indicates an important role of the uPA-uPAR-PAI-1 systems in cancer. In addition to their role in tumor cell biology, the uPA-uPAR-PAI-1 systems are also important for vascular biology by modulating angiogenesis and by altering migration of smooth muscle cells and fibrin deposition in atherosclerosis and restenosis. This review will focus on the general mechanism of uPAR/uPA/PAI-1 interactions and signaling and the possible relevance of this system in vascular biology.

Keywords

Urokinase / receptor - plasminogen activator inhibitors - angio-genesis and inhibitors - atherosclerosis - restenosis

• References

• 1 Stephens RW. et al. Plasma urokinase receptor levels in patients with colorectal cancer: relationship to prognosis. J Natl Cancer Inst 1999; 91: 869-874.
• 2 Cunningham O. et al. Dimerization controls the lipid raft partitioning of uPAR/CD87 and regulates its biological functions. EMBO J 2003; 22: 5994-6003.
• 3 Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 3: 932-943.
• 4 Liang OD. et al. Ligand binding regions in the receptor for urokinase-type plasminogen activator. J Biol Chem 2001; 276: 28946-28953.
• 5 Barinka C. et al. Structural Basis of Interaction between Urokinase-type Plasminogen Activator and its Receptor. J Mol Biol 2006; 363: 482-495.
• 6 Huai Q. et al. Structure of human urokinase plasminogen activator in complex with its receptor. Science 2006; 311: 656-659.
• 7 Huang M. et al. Crystallization of soluble urokinase receptor (suPAR) in complex with urokinase aminoterminal fragment (1–143). Acta Crystallogr D Biol Crystallogr 2005; 61: 697-700.
• 8 Hoyer-Hansen G. et al. Urokinase-catalysed cleavage of the urokinase receptor requires an intact glycolipid anchor. Biochem J 2001; 358: 673-679.
• 9 Resnati M. et al. Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect. EMBO J 1996; 15: 1572-1582.
• 10 Montuori N. et al. The cleavage of the urokinase receptor regulates its multiple functions. J Biol Chem 2002; 277: 46932-46939.
• 11 Nykjaer A. et al. Purified alpha 2-macroglobulin receptor/LDL receptor-related protein binds urokinase. plasminogen activator inhibitor type-1 complex. Evidence that the alpha 2-macroglobulin receptor mediates cellular degradation of urokinase receptorbound complexes. J Biol Chem 1992; 267: 14543-14546.
• 12 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 1998; 141: 815-828.
• 13 Godar S. et al. M6P/IGFII-receptor complexes urokinase receptor and plasminogen for activation of transforming growth factor-beta1. Eur J Immunol 1999; 29: 1004-1013.
• 14 Resnati M. et al. The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R. Proc Natl Acad Sci USA 2002; 99: 1359-1364.
• 15 Mazzieri R. et al. An uncleavable uPAR mutant allows dissection of signaling pathways in uPA-dependent cell migration. Mol Biol Cell 2006; 17: 367-378.
• 16 Mondino A, Blasi F. uPA and uPAR in fibrinolysis, immunity and pathology. Trends Immunol 2004; 25: 450-455.
• 17 Koshelnick Y. et al. Mechanisms of signaling through urokinase receptor and the cellular response. Thromb Haemost 1999; 82: 305-311.
• 18 Hoyer HG. et al. The intact urokinase receptor is required for efficient vitronectin binding: receptor cleavage prevents ligand interaction. FEBS Lett 1997; 420: 79-85.
• 19 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.
• 20 Wei Y. et al. Identification of the urokinase receptor as an adhesion receptor for vitronectin. J Biol Chem 1994; 269: 32380-32388.
• 21 Sidenius N. et al. Urokinase regulates vitronectin binding by controlling urokinase receptor oligomerization. J Biol Chem 2002; 277: 27982-27990.
• 22 Chaurasia P. et al. A region in urokinase plasminogen receptor domain III controlling a functional association with alpha5beta1 integrin and tumor growth. J Biol Chem 2006; 281: 14852-14863.
• 23 Carriero MV. et al. Urokinase receptor interacts with alphavbeta5 vitronectin receptor, promoting urokinasedependent cell migration in breast cancer. Cancer Res 1999; 59: 5307-5314.
• 24 Simon DI. et al. Mac-1 (CD11b/CD18) and the urokinase receptor (CD87) form a functional unit on monocytic cells. Blood 1996; 88: 3185-3194.
• 25 Tarui T. et al. Urokinase-type plasminogen activator receptor (CD87) is a ligand for integrins and mediates cell-cell interaction. J Biol Chem 2001; 276: 3983-3990.
• 26 Yebra M. et al. Urokinase-type plasminogen activator binding to its receptor stimulates tumor cell migration by enhancing integrin-mediated signal transduction. Exp Cell Res 1999; 250: 231-240.
• 27 Yebra M. et al. Requirement of receptor-bound urokinase-type plasminogen activator for integrin alphavbeta5- directed cell migration. J Biol Chem 1996; 271: 29393-29399.
• 28 Tarui T. et al. Critical role of integrin alpha 5 beta 1 in urokinase (uPA)/urokinase receptor (uPAR, CD87) signaling. J Biol Chem 2003; 278: 29863-29872.
• 29 Aguirre-Ghiso JA. et al. ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 2003; 63: 1684-1695.
• 30 Monaghan-Benson E. et al. Urokinase-type plasminogen activator receptor regulates a novel pathway of fibronectin matrix assembly requiring Src-dependent transactivation of epidermal growth factor receptor. J Biol Chem 2006; 281: 9450-9459.
• 31 Wei Y. et al. Regulation of alpha5beta1 integrin conformation and function by urokinase receptor binding. J Cell Biol 2005; 168: 501-511.
• 32 Aguirre Ghiso JA. et al. Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol 1999; 147: 89-104.
• 33 Aguirre-Ghiso JA. et al. 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 2001; 12: 863-879.
• 34 Guerrero J. et al. EGF receptor transactivation by urokinase receptor stimulus through a mechanism involving Src and matrix metalloproteinases. Exp Cell Res 2004; 292: 201-208.
• 35 Liu D. et al. 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.
• 36 Tsatas D. et al. EGF receptor modifies cellular responses to hyaluronan in glioblastoma cell lines. J Clin Neurosci 2002; 9: 282-288.
• 37 Wang XQ. et al. Gangliosides inhibit urokinasetype plasminogen activator (uPA)-dependent squamous carcinoma cell migration by preventing uPA receptor/ alphabeta integrin/epidermal growth factor receptor interactions. J Invest Dermatol 2005; 124: 839-848.
• 38 Furlan F. 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.
• 39 Bass R. et al. Regulation of urokinase receptor proteolytic function by the tetraspanin CD82. J Biol Chem 2005; 280: 14811-14818.
• 40 Leksa V. et al. The N-terminus of mannose 6-phosphate/ Insulin-like growth factor 2 receptor in regulation of fibrinolysis and cell migration. J Biol Chem 2002; 277: 40575-40582.
• 41 Mahdi F. et al. Mapping the interaction between high molecular mass kininogen and the urokinase plasminogen activator receptor. J Biol Chem 2004; 279: 16621-16628.
• 42 Colman RW. et al. 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 1997; 100: 1481-1487.
• 43 Colman RW. et al. Domain 5 of high molecular weight kininogen (kininostatin) down-regulates endothelial cell proliferation and migration and inhibits angiogenesis. Blood 2000; 95: 543-550.
• 44 Chavakis T. et al. Different mechanisms define the antiadhesive function of high molecular weight kininogen in integrin- and urokinase receptor-dependent interactions. Blood 2000; 96: 514-522.
• 45 Mahdi F. et al. Expression and colocalization of cytokeratin 1 and urokinase plasminogen activator receptor on endothelial cells. Blood 2001; 97: 2342-2350.
• 46 Wang XQ. et al. Ganglioside GM3 promotes carcinoma cell proliferation via urokinase plasminogen activator- induced extracellular signal-regulated kinase-independent p70S6 kinase signaling. J Invest Dermatol 2006; 126: 2687-2696.
• 47 Carmeliet P. et al. Physiological consequences of loss of plasminogen activator gene function in mice. Nature 1994; 368: 419-424.
• 48 Prager GW. et al. Vascular endothelial growth factor (VEGF) induces rapid pro-urokinase (pro-uPA) activation on the surface of endothelial cells. Blood 2003; 103: 955-962.
• 49 Kilpatrick LM. et al. Initiation of plasminogen activation on the surface of monocytes expressing the type II transmembrane serine protease matriptase. Blood 2006; 108: 2616-2623.
• 50 Moran P. et al. Pro-urokinase-type plasminogen activator is a substrate for hepsin. J Biol Chem 2006; 281: 30439-30446.
• 51 Okumura Y. et al. Serase-1B, a new splice variant of polyserase-1/TMPRSS9, activates urokinase-type plasminogen activator and the proteolytic activation is negatively regulated by glycosaminoglycans. Biochem J 2006; 400: 551-561.
• 52 Conese M, Blasi F. Urokinase/urokinase receptor system: internalization/degradation of urokinase-serpin complexes: mechanism and regulation. Biol Chem Hoppe Seyler 1995; 376: 143-155.
• 53 Dano K. et al. Plasminogen activation and cancer. Thromb Haemost 2005; 93: 676-681.
• 54 Mazar AP. The urokinase plasminogen activator receptor (uPAR) as a target for the diagnosis and therapy of cancer. Anticancer Drugs 2001; 12: 387-400.
• 55 Dano K. et al. Cancer invasion and tissue remodeling-- cooperation of protease systems and cell types. APMIS 1999; 107: 120-127.
• 56 Leksa V. et al. TGF-beta-induced apoptosis in endothelial cells mediated by M6P/IGFII-R and miniplasminogen. J Cell Sci 2005; 118: 4577-4586.
• 57 Wei Y. et al. A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling. J Cell Biol 1999; 144: 1285-1294.
• 58 Wei Y. et al. Urokinase receptors promote beta1 integrin function through interactions with integrin alpha3beta1. Mol Biol Cell 2001; 12: 2975-2986.
• 59 Fazioli F. et al. A urokinase-sensitive region of the human urokinase receptor is responsible for its chemotactic activity. EMBO J 1997; 16: 7279-7286.
• 60 Degryse B. et al. Src-dependence and pertussistoxin sensitivity of urokinase receptor-dependent chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. Blood 1999; 94: 649-662.
• 61 Nguyen DH. 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 2000; 275: 19382-19388.
• 62 Fazioli F. et al. A urokinase-sensitive region of the human urokinase receptor is responsible for its chemotactic activity. EMBO J 1997; 16: 7279-7286.
• 63 Resnati M. et al. The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R. Proc Natl Acad Sci USA 2002; 99: 1359-1364.
• 64 Ma Z. et al. Regulation of Rac1 activation by the low density lipoprotein receptor-related protein. J Cell Biol 2002; 159: 1061-1070.
• 65 Bohuslav J. 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: 1381-1390.
• 66 Koshelnick Y. et al. Urokinase receptor is associated with the components of the JAK1/STAT1 signaling pathway and leads to activation of this pathway upon receptor clustering in the human kidney epithelial tumor cell line TCL-598. J Biol Chem 1997; 272: 28563-28567.
• 67 Dumler I. et al. The Jak/Stat pathway and urokinase receptor signaling in human aortic vascular smooth muscle cells. J Biol Chem 1998; 273: 315-321.
• 68 Dumler I. et al. Urokinase induces activation and formation of Stat4 and Stat1-Stat2 complexes in human vascular smooth muscle cells. J Biol Chem 1999; 274: 24059-24065.
• 69 Kiian I. et al. Urokinase-induced migration of human vascular smooth muscle cells requires coupling of the small GTPases RhoA and Rac1 to the Tyk2/PI3-K signalling pathway. Thromb Haemost 2003; 89: 904-914.
• 70 Kusch A. et al. Urokinase stimulates human vascular smooth muscle cell migration via a phosphatidylinositol 3-kinase-Tyk2 interaction. J Biol Chem 2000; 275: 39466-39473.
• 71 Kiyan J. et al. Urokinase-induced signaling in human vascular smooth muscle cells is mediated by PDGFR-beta. EMBO J 2005; 24: 1787-1797.
• 72 Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000; 6: 389-395.
• 73 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407: 249-257.
• 74 Carmeliet P. Angiogenesis in health and disease. Nat Med 2003; 9: 653-660.
• 75 Carmeliet P. Blood vessels and nerves: common signals, pathways and diseases. Nat Rev Genet 2003; 4: 710-720.
• 76 Carmeliet P. VEGF as a key mediator of angiogenesis in cancer. Oncology 2005; 69 (Suppl. 03) (Suppl) 4-10.
• 77 Carmeliet P. et al. Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system. Ann NY Acad Sci 1997; 811: 191-206.
• 78 Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005; 438: 932-936.
• 79 Goldman E. The growth of malignant disease in man and the lower animals with special reference to the vascular system. Lancet 1907; 2: 1236-1240.
• 80 Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285: 1182-1186.
• 81 Min HY. et al. Urokinase receptor antagonists inhibit angiogenesis and primary tumor growth in syngeneic mice. Cancer Res 1996; 56: 2428-2433.
• 82 Ossowski L. Effect of antisense inhibition of Urokinase receptor on malignancy. Curr Top Microbiol Immunol 1996; 213: 101-112.
• 83 Bajou K. et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 1998; 4: 923-928.
• 84 Brooks PC. et al. Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell 1998; 92: 391-400.
• 85 Felsenfeld DP. et al. Ligand binding regulates the directed movement of beta1 integrins on fibroblasts. Nature 1996; 383: 438-440.
• 86 Lauffenburger DA, Horwitz AF. Cell migration: a physically integrated molecular process. Cell 1996; 84: 359-369.
• 87 Lawson MA, Maxfield FR. Ca(2+)- and calcineurin- dependent recycling of an integrin to the front of migrating neutrophils. Nature 1995; 377: 75-79.
• 88 Zoellner H. et al. Inhibition of microvascular endothelial apoptosis in tissue explants by serum albumin. Microvasc Res 1999; 57: 162-173.
• 89 Li Y. et al. The YXXL motif, but not the two NPXY motifs, serves as the dominant endocytosis signal for low density lipoprotein receptor-related protein. J Biol Chem 2000; 275: 17187-17194.
• 90 Fabbri M. et al. A tyrosine-based sorting signal in the beta2 integrin cytoplasmic domain mediates its recycling to the plasma membrane and is required for ligand- supported migration. EMBO J 1999; 18: 4915-4925.
• 91 Prager GW. et al. Vascular endothelial growth factor (VEGF) induces rapid prourokinase (pro-uPA) activation on the surface of endothelial cells. Blood 2004; 103: 955-962.
• 92 Herz J. et al. LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell 1992; 71: 411-421.
• 93 Nykjaer A. et al. Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. EMBO J 1997; 16: 2610-2620.
• 94 Prager GW. duced initial endothelial cell migration depends on the presence of the urokinase receptor. Circ Res 2004; 94: 1562-1570.
• 95 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 2001; 152: 777-784.
• 96 Bajou K. et al. Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth. Oncogene 2004; 23: 6986-6990.
• 97 Devy L. et al. The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J 2002; 16: 147-154.
• 98 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27-31.
• 99 Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002; 29 (Suppl. 16) (Suppl) 15-18.
• 100 Hajitou A. et al. The antitumoral effect of endostatin and angiostatin is associated with a down-regulation of vascular endothelial growth factor expression in tumor cells. FASEB J 2002; 16: 1802-1804.
• 101 Tarui T. et al. Specific interaction of angiostatin with integrin alpha(v)beta(3) in endothelial cells. J Biol Chem 2001; 276: 39562-39568.
• 102 Carmeliet P. Proteinases in cardiovascular aneurysms and rupture: targets for therapy?. J Clin Invest 2000; 105: 1519-1520.
• 103 Carmeliet P. et al. Urokinase but not tissue plasminogen activator mediates arterial neointima formation in mice. Circ Res 1997; 81: 829-839.
• 104 Carmeliet P. et al. Biological effects of disruption of the tissue-type plasminogen activator, urokinasetype plasminogen activator, and plasminogen activator inhibitor-1 genes in mice. Ann NY Acad Sci 1995; 748: 367-381.
• 105 Smith LH. et al. Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis. Blood 2006; 107: 132-134.
• 106 Eren M. et al. Age-dependent spontaneous coronary arterial thrombosis in transgenic mice that express a stable form of human plasminogen activator inhibitor- 1. Circulation 2002; 106: 491-496.
• 107 Asselbergs FW. et al. Gender-specific correlations of PAI-1 and t-PA levels with cardiovascular diseaserelated traits. J Thromb Haemost. 2006 epub ahead of print
• 108 De Taeye B. et al. Plasminogen activator inhibitor- 1: a common denominator in obesity, diabetes and cardiovascular disease. Curr Opin Pharmacol 2005; 5: 149-154.
• 109 Vaughan DE. PAI-1 and atherothrombosis. J Thromb Haemost 2005; 3: 1879-1883.
• 110 Vaughan DE. Plasminogen activator inhibitor-1 and the calculus of mortality after myocardial infarction. Circulation 2003; 108: 376-377.
• 111 Vaughan DE. Plasminogen activator inhibitor-1: a common denominator in cardiovascular disease. J Investig Med 1998; 46: 370-376.
• 112 Christ G. et al. Plasmin activation system in restenosis: role in pathogenesis and clinical prediction?. J Thromb Thrombolysis 1999; 7: 277-285.
• 113 Christ G. et al. Predictive value of plasma plasminogen activator inhibitor-1 for coronary restenosis: dependence on stent implantation and antithrombotic medication. J Thromb Haemost 2005; 3: 233-239.
• 114 Geppert A. et al. Concentration of endogenous tPA antigen in coronary artery disease: relation to thrombotic events, aspirin treatment, hyperlipidemia, and multivessel disease. Arterioscler Thromb Vasc Biol 1998; 18: 1634-1642.
• 115 Geppert A. et al. Plasminogen activator inhibitor type 1 and outcome after successful cardiopulmonary resuscitation. Crit Care Med 2001; 29: 1670-1677.
• 116 Gottsauner-Wolf M. et al. Predictive value of PAI-1 plasma activity and thallium perfusion imaging for restenosis after percutaneous transluminal angioplasty in clinically asymptomatic patients. Thromb Haemost 1999; 81: 522-526.
• 117 Peng L. et al. Endogenous vitronectin and plasminogen activator inhibitor-1 promote neointima formation in murine carotid arteries. Arterioscler Thromb Vasc Biol 2002; 22: 934-939.
• 118 Zhu Y. et al. Plasminogen activator inhibitor type 1 enhances neointima formation after oxidative vascular injury in atherosclerosis-prone mice. Circulation 2001; 103: 3105-3110.
• 119 Ploplis VA, Castellino FJ. Attenuation of neointima formation following arterial injury in PAI-1 deficient mice. Ann NY Acad Sci 2001; 936: 466-468.
• 120 Ploplis VA. et al. Enhanced in vitro proliferation of aortic endothelial cells from plasminogen activator inhibitor- 1-deficient mice. J Biol Chem 2004; 279: 6143-6151.
• 121 Vaughan DE. PAI-1 and cellular migration: dabbling in paradox. Arterioscler Thromb Vasc Biol 2002; 22: 1522-1523.
• 122 Kunigal S. et al. Monocyte-expressed urokinase inhibits vascular smooth muscle cell growth by activating Stat1. Blood 2003; 102: 4377-4383.