Download PDF
Thromb Haemost 1999; 82(S 01): 19-22
DOI: 10.1055/s-0037-1615547
Commentaries
Schattauer GmbH

Structure and Function of the Urokinase Receptor

Anna Mondino
1   From the Dipartimento di Patologia e Medicina Molecolare, Università Vita-Salute San Raffaele, Milan, Italy
,
Massimo Resnati
1   From the Dipartimento di Patologia e Medicina Molecolare, Università Vita-Salute San Raffaele, Milan, Italy
,
Francesco Blasi
1   From the Dipartimento di Patologia e Medicina Molecolare, Università Vita-Salute San Raffaele, Milan, Italy
› Author Affiliations
Further Information

Publication History

Publication Date:
14 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

The binding of the urokinase plasminogen activator (uPA) to its receptor (uPAR) regulates cell adhesion, surface proteolysis, chemotaxis and cell extravasation in a number of experimental systems. Recent evidences have suggested that uPAR can by itself mediate chemotaxis of human monocytes and cause profound changes in cytoskeletal organization indicating that this receptor has the properties of a cell-surface regulated chemokine. Indeed, it is likely that upon binding to uPA, uPAR undergoes a conformational change that uncovers a new epitope located in the linker region between domain 1 and 2 of the receptor and is endowed with a potent chemotactic activity. This conformational change can be mimicked in vitro by enzymatic processing of a recombinant receptor. We have shown that chymotrypsin cleaves uPAR between domain 1 and 2 in an area that can be also cleaved by uPA at high efficiency and generate a receptor that can mediate monocytes migration independently of uPA binding. This mechanism is pertussis-toxin sensitive and involves activation of tyrosine kinases and cytoskeletal reorganization events in vitro. These studies indicate that in addition to its receptor function, upon binding to uPA, uPAR becomes a pleiotropic ligand for other still to be identified surface molecules.

Key words

Urokinase receptor - chemotaxis - cytoskeleton - tyrosine kinases - G-proteins
 

  • References

  • 1 Danø K, Andreasen PA, Grandal-Hansen J, Krsitensen P, Nielsen LS, Skriver L. Plasminogen activators, tissue degradation and cancer. Adv Cancer Res 1985; 44: 139-266.
    CrossrefPubMedGoogle Scholar
  • 2 Fazioli F, Resnati M, Sidenius N, Higashimoto Y, Appella E, Blasi F. The urokinase-sensitive region of the urokinase receptor is responsible for its potent chemotactic activity. EMBO J 1997; 16: 7279-86.
    CrossrefPubMedGoogle Scholar
  • 3 Baggiolini M, Dewald B, Moser B. Interleukin-8 and related chemotactic chemokines-CXC and CC chemokines. Adv Immunol 1994; 55: 97-179.
    PubMedGoogle Scholar
  • 4 Premack BA, Schall TJ. Chemokine receptors: gateways to inflammation and infection. Nature Med. 1996 2. 11748.
    PubMedGoogle Scholar
  • 5 Gyetko MR, Chen G-H, McDonald RA, Goodman R, Huffnagle GB, Wilkinson CC, Fuller JA, Toews GB. Urokinase is required for the pulmonary inflammatory response to Cryptococcus neoformans. J Clin Invest 1996; 97: 1818-26.
    CrossrefPubMedGoogle Scholar
  • 6 May AE, Kanse SM, Rund LR, Gisler RH, Imhof BA, Preissner K. Urokinase receptor (uPAR) regulates a leukocyte recruitment via p2 integrins in vivo. J Exp Med 1998; 188: 1029-37.
    CrossrefPubMedGoogle Scholar
  • 7 Shapiro RL, Duquette JG, Roses DF, Nunes I, Harris MN, Kamino H, Wilson EL, Rifkin DB. Induction of primary cutaneous melanocytic neoplasms in utokinase-type plasminogen activator (uPA)-deficient and wild type mice: cellular bleu nevi invade but do not progress to malignant melanoma in uPA-deficient animals. Cancer Res 1996; 56: 3597-604.
    PubMedGoogle Scholar
  • 8 Pedersen TL, Yong K, Pedersen JO, Hansen NE, Danø K, Plesner T. Impaired migration in vitro of neutrophils from patients with paroxysmal nocturnal hemoglobinuria. Brit J Haematol 1996; 95: 45-51.
    PubMedGoogle Scholar
  • 9 Heiss MM, Allgayer H, Gruetzner KU, Funke I, Babic R, Jauch K-W, Schildberg FW. Individual development and uPA-receptor expression of disseminated tumour cells in bone marrow: a reference to early systemic disease in solid cancer. Nature Medicine 1995; 1: 1035-9.
    CrossrefPubMedGoogle Scholar
  • 10 Sier CFM, Stephens R, Bizik J, Mariani A, Bassan M, Pedersen N, Frigerio L, Ferrari A, Danø K, Brunner N, Blasi F. Full-size, GPI-anchor free urokinase receptor is increased in serum of ovarian cancer patients. Cancer Res 1998; 58: 1843-9.
    PubMedGoogle Scholar
  • 11 Romer J, Bugge TH, Pyke C, Lund LR, Flick MJ, Degen JL, Danø K. Impaired wound healing in mice with a disrupted plasminogen gene. Nature Med 1996; 2: 287-92.
    CrossrefPubMedGoogle Scholar
  • 12 Blasi F. Urokinase and urokinase receptor: A paracrine/autocrine system regulating cell migration and invasiveness. BioEssays 1993; 15: 105-11.
    CrossrefPubMedGoogle Scholar
  • 13 Andreasen PA, Georg B, Lund LR, Riccio A, Stacey SN. Plasminogen activator inhibitors: hormonally regulated serpins. Mol Cell Endocrinol 1990; 88: 1-19.
    PubMedGoogle Scholar
  • 14 Cubellis MV, Wun T-C, Blasi F. Receptor-mediated internalization and degradation of urokinase-PAI-1 complex in human U937 cells. EMBO J 1990; 9: 1079-85.
    PubMedGoogle Scholar
  • 15 Nykiær A, Petersen CM, Møller B, Jensen PH, Moestrup SK, Holtet TL, Etzerodt M, Thøgersen HC, Munch M, Andreasen PA, Gliemann J. Purified a2 macroglobulin receptor/LDL receptor related protein binds urokinase-plasminogen activator inhibitor type-1 complex. Evidence that a2 macroglobulin receptor mediates cellular degradation of urokinase receptorbound complexes. J Biol Chem 1992; 267: 14543-6.
    PubMedGoogle Scholar
  • 16 Conese M, Nykjær A, Christensen EI, Petersen CM, Cremona O, Pardi R, Andreasen PA, Gliemann J, Blasi F. Alpha-2 macroglobulin receptordependent internalization of the urokinase receptor. J Cell Biol 1995; 131: 1609-22.
    CrossrefPubMedGoogle Scholar
  • 17 Nykjær A, Conese M, Christensen EI, Olson D, Cremona O, Gliemann J, Blasi F. Recycling of the urokinase receptor during internalization of the uPA-serpin complexes. EMBO J 1997; 16: 2610-20.
    CrossrefPubMedGoogle Scholar
  • 18 Bugge TH, Flick MJ, Daugherty CC, Degen JL. Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction. Genes and Development 1995; 9: 794-807.
    CrossrefPubMedGoogle Scholar
  • 19 Carmeliet P, Schoojans L, Kieckens L, Ream B, Degen JL, Bronson R, DeVos R, van den Oord JJ, Collen D, Mulligan RC. Physiological consequences of loss plasminogen activator gene function in mice. Nature 1994; 368: 419-24.
    CrossrefPubMedGoogle Scholar
  • 20 Bugge TH, Suh TT, Flick MJ, Daugherty CC, Rømer J, Solberg H, Ellis VJ, Danø K, Degen JL. The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility. J Biol Chem 1995; 270: 16886-94.
    CrossrefPubMedGoogle Scholar
  • 21 Bugge TH, Flick MJ, Danton MJS, Daugherty CC, Ramer J, Dano K, Carmeliet P, Collen D, Degen JL. 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 1996; 93: 5899-904.
    CrossrefPubMedGoogle Scholar
  • 22 Naldini L, Tamagnone L, Vigna E, Sachs M, Hartmann G, Birchmeier W, Daikuhara Y, Tsubouchi H, Blasi F, Comoglio PM. Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor. EMBO J 1992; 11: 4825-33.
    PubMedGoogle Scholar
  • 23 Sato Y, Rifkin D. Autocrine activity of basic fibroblast growth factor: regulation of endothelial cell movement, plasminogen activator synthesis, and DNA synthesis. J Cell Biol 1988; 107: 1199-205.
    CrossrefPubMedGoogle Scholar
  • 24 Sato YR, Rifkin DB. Inhibition of endothelial cell movement by perycites and smooth muscle cells: Activation of a latent transforming growth factor 1-like molecule by plasmin during co-culture. J Cell Biol 1990; 109: 309-15.
    PubMedGoogle Scholar
  • 25 Pollanen J, Saksela O, Salonen E-M, Andreasen P, Nielsen L, Dano K, Vaheri A. Distinct localization of urokinase-type plasminogen activator and its type-1 inhibitor under cultured human fibroblasts and sarcoma cells. J Cell Biol 1987; 104: 1085-96.
    CrossrefPubMedGoogle Scholar
  • 26 Pollanen J, Hedman K, Nielsen LS, Dano K, Vaheri A. Ultrastructural localization of plasma membrane-associated urokinase-type plasminogen activator at focal contact sites. J Cell Biol 1988; 106: 87-95.
    CrossrefPubMedGoogle Scholar
  • 27 Estreicher A, Muhlhauser J, Carpentier J-L, Orci L, Vassalli J-D. The receptor for urokinase-type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes. J Cell Biol 1990; 111: 783-92.
    CrossrefPubMedGoogle Scholar
  • 28 Resnati M, Guttinger M, Valcamonica S, Sidenius N, Blasi F, Fazioli F. Proteolytic cleavage of the urokinase receptor substitutes foir the agonistinduced chemotactic effect. EMBO J 1996; 15: 1572-82.
    PubMedGoogle Scholar
  • 29 Myohanen HT, Stephens RW, Hedman K, Tapiovaara H, Ranne E, Hoyer-Hansen G, Dano K, Vaheri A. Distribution and lateral mobility of the urokinase receptor complex at the cell surface. J Histochem. Cytochem 1993; 41: 1291-301.
    CrossrefPubMedGoogle Scholar
  • 30 Pepper MS, Sappino A-P, Stocklin R, Montesano R, Orci L, Vassalli J-D. Upregulation of urokinase receptor expression on migrating endothelial cells. J Cell Biol 1993; 122: 673-84.
    CrossrefPubMedGoogle Scholar
  • 31 Blasi F. uPAR-uPA-PAI-1: a key intersection in proteolysis, adhesion and chemotaxis. Immunol Today 1997; 18: 415-7.
    CrossrefPubMedGoogle Scholar
  • 32 Fibbi G, Ziche M, Morbidelli L, Magnelli L, Del Rosso M. Interaction of urokinase with specific receptors stimulates mobilization of bovine adrenal capillary endothelial cells. Exp Cell Res 1988; 179: 385-95.
    CrossrefPubMedGoogle Scholar
  • 33 Gudewicz PW, Bilboa N. Human urokinase-type plasminogen activator stimulates chemotaxis of human neutrophils. Biochem. Biophys. Res Comm 1987; 147: 1176-81.
    PubMedGoogle Scholar
  • 34 Boyle MDP, Chiodo VA, Lawman MJP, Gee AP, Young M. Urokinase: a chemotactic factor for polymorphonuclear leukocytes in vivo. J Immunol 1987; 139: 169-74.
    PubMedGoogle Scholar
  • 35 Gyetko MR, Todd RF, Wilkinson CC, Sitrin RG. The urokinase receptor is required for human monocyte chemotaxis in vitro. J Clin Invest 1994; 93: 1380-7.
    CrossrefPubMedGoogle Scholar
  • 36 Hoyer-Hansen G, Ploug M, Behrendt N, Ranne E, Dano K. Cell surface acceleration of urokinase-catalyzed receptor cleavage. Eur J Biochem 1997; 243: 21-6.
    CrossrefPubMedGoogle Scholar
  • 37 Waltz DA, Chapman Jr. HA. Reversible cellular adhesion to vitronectin linked to urokinase receptor occupancy. J Biol Chem 1994; 269: 14746-50.
    PubMedGoogle Scholar
  • 38 Wie Y, Waltz DA, Rao N, Drummond RJ, Rosenberg S, Chapman Jr. HA. Identification of the urokinase receptor as an adhesion receptor for vitronectin. J Biol Chem 1994; 269: 32380-8.
    PubMedGoogle Scholar
  • 39 Wei Y, Lukashev M, Simon DI, Bodary SC, Rosenberg S, Doyle MV, Chapman HA. Regulation of integrin function by the urokinase receptor. Science 1996; 273: 1551-5.
    CrossrefPubMedGoogle Scholar
  • 40 Deng G, Curriden SA, Wang S, Rosenberg S, Loskutoff DJ. Is plasminogen activator inhibitor-1 the molecular switch that governs the urokinase receptor-mediated cell adhesion and release?. J Cell Biol 1996; 134: 1563-71.
    CrossrefPubMedGoogle Scholar
  • 41 Kanse SM, Kost C, Wilhelm OG, Andreasen PA, Preissner KT. The urokinase receptor is a major vitronectin,-binding protein on endothelial cells. Exp Cell Res 1996; 224: 344-53.
    CrossrefPubMedGoogle Scholar
  • 42 Simon DI, Rao NK, Xu H, Wei Y, Majdic O, Ranne E, Kobzik L, Chapman Jr. HA. Mac-1 (CD11b/CD18) and the urokinase receptor (CD87) form a functional unit on monocytic cells. Blood 1996; 88: 3185-94.
    PubMedGoogle Scholar
  • 43 Bohuslav J, Horejsi V, Hansmann C, Stockl J, Weidle UH, Majdic O, Bartke I, Knapp W, Stockinger H. Urokinase plasminogen activator receptor, beta-2 integrins, and Src-kinases within a single receptor complex of human monocytes. J Exp Med 1995; 181: 1381-90.
    CrossrefPubMedGoogle Scholar
  • 44 Xue W, Kindzelskii AL, Todd RF, Petty HR. Physical association of complement receptor type 3 and urokinase-type plasminogen activator receptor in neutrophil membranes. J Immunol 1994; 152: 4630-40.
    PubMedGoogle Scholar
  • 45 Springer TtA, Anderson DC. The importance of the Mac-1, LFA-1 glycoprotein family in monocyte and granulocyte adherence, chemotaxis and migration into inflammatory sites: insights from an experiment in nature. In Biochemistry of Macrophages (Ciba Foundation Symposium 118). Evered D, Nugent J, O'Connor M. eds London: Pittman; 1986: 102-26.
    Google Scholar
  • 46 Huttenlocher A, Ginsberg MH, Horwitz AF. Modulation of cell migration by integrin-mediated cytoskeletal linkages and ligand-binding affinity. J Cell Biol 1996; 134: 1551-62.
    CrossrefPubMedGoogle Scholar