• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of embojLink to Publisher's site
EMBO J. Dec 15, 1997; 16(24): 7279–7286.
PMCID: PMC1170328

A urokinase-sensitive region of the human urokinase receptor is responsible for its chemotactic activity.

Abstract

The role of urokinase-type plasminogen activator (uPA) and its receptor (uPAR/CD87) in cell migration and invasion is well substantiated. Recently, uPA has been shown to be essential in cell migration, since uPA-/- mice are greatly impaired in inflammatory cell recruitment. We have shown previously that the uPA-induced chemotaxis requires interaction with and modification of uPAR/CD87, which is the true chemoattracting molecule acting through an unidentified cell surface component which mediates this cell surface chemokine activity. By expressing and testing several uPAR/CD87 variants, we have located and functionally characterized a potent uPAR/CD87 epitope that mimics the effects of the uPA-uPAR interaction. The chemotactic activity lies in the region linking domains 1 and 2, the only protease-sensitive region of uPAR/CD87, efficiently cleaved by uPA at physiological concentrations. Synthetic peptides carrying this epitope promote chemotaxis and activate p56/p59(hck) tyrosine kinase. Both chemotaxis and kinase activation are pertussis toxin sensitive, involving a Gi/o protein in the pathway.

Full Text

The Full Text of this article is available as a PDF (377K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Appella E, Robinson EA, Ullrich SJ, Stoppelli MP, Corti A, Cassani G, Blasi F. The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. J Biol Chem. 1987 Apr 5;262(10):4437–4440. [PubMed]
  • Baggiolini M, Dewald B, Moser B. Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines. Adv Immunol. 1994;55:97–179. [PubMed]
  • Behrendt N, Ploug M, Patthy L, Houen G, Blasi F, Danø K. The ligand-binding domain of the cell surface receptor for urokinase-type plasminogen activator. J Biol Chem. 1991 Apr 25;266(12):7842–7847. [PubMed]
  • Bianchi E, Cohen RL, Thor AT, Todd RF, 3rd, Mizukami IF, Lawrence DA, Ljung BM, Shuman MA, Smith HS. The urokinase receptor is expressed in invasive breast cancer but not in normal breast tissue. Cancer Res. 1994 Feb 15;54(4):861–866. [PubMed]
  • Bianchi E, Ferrero E, Fazioli F, Mangili F, Wang J, Bender JR, Blasi F, Pardi R. Integrin-dependent induction of functional urokinase receptors in primary T lymphocytes. J Clin Invest. 1996 Sep 1;98(5):1133–1141. [PMC free article] [PubMed]
  • Blasi F. uPA, uPAR, PAI-1: key intersection of proteolytic, adhesive and chemotactic highways? Immunol Today. 1997 Sep;18(9):415–417. [PubMed]
  • Bohuslav J, Horejsí V, Hansmann C, Stöckl 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 Apr 1;181(4):1381–1390. [PMC free article] [PubMed]
  • Busso N, Masur SK, Lazega D, Waxman S, Ossowski L. Induction of cell migration by pro-urokinase binding to its receptor: possible mechanism for signal transduction in human epithelial cells. J Cell Biol. 1994 Jul;126(1):259–270. [PMC free article] [PubMed]
  • Dewerchin M, Nuffelen AV, Wallays G, Bouché A, Moons L, Carmeliet P, Mulligan RC, Collen D. Generation and characterization of urokinase receptor-deficient mice. J Clin Invest. 1996 Feb 1;97(3):870–878. [PMC free article] [PubMed]
  • Estreicher A, Wohlwend A, Belin D, Schleuning WD, Vassalli JD. Characterization of the cellular binding site for the urokinase-type plasminogen activator. J Biol Chem. 1989 Jan 15;264(2):1180–1189. [PubMed]
  • 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 Dec;179(2):385–395. [PubMed]
  • Grøndahl-Hansen J, Peters HA, van Putten WL, Look MP, Pappot H, Rønne E, Dano K, Klijn JG, Brünner N, Foekens JA. Prognostic significance of the receptor for urokinase plasminogen activator in breast cancer. Clin Cancer Res. 1995 Oct;1(10):1079–1087. [PubMed]
  • Gudewicz PW, Gilboa N. Human urokinase-type plasminogen activator stimulates chemotaxis of human neutrophils. Biochem Biophys Res Commun. 1987 Sep 30;147(3):1176–1181. [PubMed]
  • Gyetko MR, Chen GH, McDonald RA, Goodman R, Huffnagle GB, Wilkinson CC, Fuller JA, Toews GB. Urokinase is required for the pulmonary inflammatory response to Cryptococcus neoformans. A murine transgenic model. J Clin Invest. 1996 Apr 15;97(8):1818–1826. [PMC free article] [PubMed]
  • Gyetko MR, Todd RF, 3rd, Wilkinson CC, Sitrin RG. The urokinase receptor is required for human monocyte chemotaxis in vitro. J Clin Invest. 1994 Apr;93(4):1380–1387. [PMC free article] [PubMed]
  • Høyer-Hansen G, Rønne E, Solberg H, Behrendt N, Ploug M, Lund LR, Ellis V, Danø K. Urokinase plasminogen activator cleaves its cell surface receptor releasing the ligand-binding domain. J Biol Chem. 1992 Sep 5;267(25):18224–18229. [PubMed]
  • Høyer-Hansen G, Ploug M, Behrendt N, Rønne E, Danø K. Cell-surface acceleration of urokinase-catalyzed receptor cleavage. Eur J Biochem. 1997 Jan 15;243(1-2):21–26. [PubMed]
  • Kindzelskii AL, Laska ZO, Todd RF, 3rd, Petty HR. Urokinase-type plasminogen activator receptor reversibly dissociates from complement receptor type 3 (alpha M beta 2' CD11b/CD18) during neutrophil polarization. J Immunol. 1996 Jan 1;156(1):297–309. [PubMed]
  • Masucci MT, Pedersen N, Blasi F. A soluble, ligand binding mutant of the human urokinase plasminogen activator receptor. J Biol Chem. 1991 May 15;266(14):8655–8658. [PubMed]
  • 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 May 15;56(10):2428–2433. [PubMed]
  • Neer EJ. Heterotrimeric G proteins: organizers of transmembrane signals. Cell. 1995 Jan 27;80(2):249–257. [PubMed]
  • Nykjaer A, Møller B, Todd RF, 3rd, Christensen T, Andreasen PA, Gliemann J, Petersen CM. Urokinase receptor. An activation antigen in human T lymphocytes. J Immunol. 1994 Jan 15;152(2):505–516. [PubMed]
  • Pallisgaard N, Pedersen FS, Birkelund S, Jørgensen P. A common multiple cloning site in a set of vectors for expression of eukaryotic genes in mammalian, insect and bacterial cells. Gene. 1994 Jan 28;138(1-2):115–118. [PubMed]
  • Picone R, Kajtaniak EL, Nielsen LS, Behrendt N, Mastronicola MR, Cubellis MV, Stoppelli MP, Pedersen S, Danø K, Blasi F. Regulation of urokinase receptors in monocytelike U937 cells by phorbol ester phorbol myristate acetate. J Cell Biol. 1989 Feb;108(2):693–702. [PMC free article] [PubMed]
  • Pizza M, Covacci A, Bartoloni A, Perugini M, Nencioni L, De Magistris MT, Villa L, Nucci D, Manetti R, Bugnoli M, et al. Mutants of pertussis toxin suitable for vaccine development. Science. 1989 Oct 27;246(4929):497–500. [PubMed]
  • 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 Aug 1;349(2):163–168. [PubMed]
  • Ploug M, Rønne E, Behrendt N, Jensen AL, Blasi F, Danø K. Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol. J Biol Chem. 1991 Jan 25;266(3):1926–1933. [PubMed]
  • Ploug M, Ellis V, Danø K. Ligand interaction between urokinase-type plasminogen activator and its receptor probed with 8-anilino-1-naphthalenesulfonate. Evidence for a hydrophobic binding site exposed only on the intact receptor. Biochemistry. 1994 Aug 2;33(30):8991–8997. [PubMed]
  • 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 May;138(5):1059–1067. [PMC free article] [PubMed]
  • Pyke C, Graem N, Ralfkiaer E, Rønne E, Høyer-Hansen G, Brünner N, Danø K. Receptor for urokinase is present in tumor-associated macrophages in ductal breast carcinoma. Cancer Res. 1993 Apr 15;53(8):1911–1915. [PubMed]
  • Resnati M, Guttinger M, Valcamonica S, Sidenius N, Blasi F, Fazioli F. Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect. EMBO J. 1996 Apr 1;15(7):1572–1582. [PMC free article] [PubMed]
  • Roldan AL, Cubellis MV, Masucci MT, Behrendt N, Lund LR, Danø K, Appella E, Blasi F. Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin dependent proteolysis. EMBO J. 1990 Feb;9(2):467–474. [PMC free article] [PubMed]
  • Shapiro RL, Duquette JG, Roses DF, Nunes I, Harris MN, Kamino H, Wilson EL, Rifkin DB. 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 Aug 1;56(15):3597–3604. [PubMed]
  • Solberg H, Rømer J, Brünner N, Holm A, Sidenius N, Danø K, Høyer-Hansen G. A cleaved form of the receptor for urokinase-type plasminogen activator in invasive transplanted human and murine tumors. Int J Cancer. 1994 Sep 15;58(6):877–881. [PubMed]
  • 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 U S A. 1985 Aug;82(15):4939–4943. [PMC free article] [PubMed]
  • Stoppelli MP, Tacchetti C, Cubellis MV, Corti A, Hearing VJ, Cassani G, Appella E, Blasi F. Autocrine saturation of pro-urokinase receptors on human A431 cells. Cell. 1986 Jun 6;45(5):675–684. [PubMed]
  • Ulevitch RJ, Tobias PS. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu Rev Immunol. 1995;13:437–457. [PubMed]
  • Wei Y, Lukashev M, Simon DI, Bodary SC, Rosenberg S, Doyle MV, Chapman HA. Regulation of integrin function by the urokinase receptor. Science. 1996 Sep 13;273(5281):1551–1555. [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links