Skip to main content

Advertisement

SpringerLink
Log in

Urokinase Receptor Orchestrates the Plasminogen System in Airway Epithelial Cell Function

  • Published:
Lung Aims and scope Submit manuscript

Abstract

Purpose

The plasminogen system plays many roles in normal epithelial cell function, and components are elevated in diseases, such as cancer and asthma. The relative contribution of each component to epithelial function is unclear. We characterized normal cell function in airway epithelial cells with increased expression of selected pathway components.

Methods

BEAS-2B R1 bronchial epithelial cells stably overexpressing membrane urokinase plasminogen activator receptor (muPAR), soluble spliced uPAR (ssuPAR), the ligand (uPA) or inhibitors (PAI1 or PAI2), were characterized for pathway expression. Cell function was examined using proliferation, apoptosis, and scratch wound assays. A549 alveolar epithelial cells overexpressing muPAR were similarly characterized and downstream plasmin activity, MMP-1, and MMP-9 measured.

Results

Elevated expression of individual components led to changes in the plasminogen system expression profile, indicating coordinated regulation of the pathway. Increased muPAR expression augmented wound healing rate in BEAS-2B R1 and attenuated repair in A549 cells. Elevated expression of other system components had no effect on cell function in BEAS-2B R1 cells. This is the first study to investigate activity of the splice variant ssuPAR, with results suggesting that this variant plays a limited role in epithelial cell function in this model.

Conclusions

Our data highlight muPAR as the critical molecule orchestrating effects of the plasminogen system on airway epithelial cell function. These data have implications for diseases, such as cancer and asthma, and suggest uPAR as the key therapeutic target for the pathway in approaches to alter epithelial cell function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

COPD:

Chronic obstructive pulmonary disease

GPI:

Glycosylphosphatidylinositol

MMP:

Matrix metalloproteinase

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

muPAR:

Membrane-bound urokinase plasminogen activator receptor

PAI1:

Plasminogen activator inhibitor 1

PAI2:

Plasminogen activator inhibitor 2

Q-PCR:

Quantitative polymerase chain reaction

scuPAR:

Soluble cleaved uPAR

ssuPAR:

Soluble spliced uPAR

uPA:

Urokinase plasminogen activator

VN:

Vitronectin

References

  1. Collen D (1999) The plasminogen (fibrinolytic) system. Thromb Haemost 82(2):259–270

    PubMed  CAS  Google Scholar 

  2. Carmeliet P, Moons L, Lijnen R, Baes M, Lemaitre V, Tipping P, Drew A, Eeckhout Y, Shapiro S, Lupu F, Collen D (1997) Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet 17(4):439–444. doi:10.1038/ng1297-439

    Article  PubMed  CAS  Google Scholar 

  3. Estreicher A, Muhlhauser J, Carpentier JL, Orci L, Vassalli JD (1990) 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 111(2):783–792

    Article  PubMed  CAS  Google Scholar 

  4. Lyons RM, Gentry LE, Purchio AF, Moses HL (1990) Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol 110(4):1361–1367

    Article  PubMed  CAS  Google Scholar 

  5. Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N (1992) Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. The Journal of biological chemistry 267(36):26031–26037

    PubMed  CAS  Google Scholar 

  6. Chapman HA, Wei Y, Simon DI, Waltz DA (1999) Role of urokinase receptor and caveolin in regulation of integrin signaling. Thromb Haemost 82(2):291–297

    PubMed  CAS  Google Scholar 

  7. Smith HW, Marshall CJ (2010) Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol 11(1):23–36. doi:10.1038/nrm2821

    Article  PubMed  CAS  Google Scholar 

  8. Montuori N, Visconte V, Rossi G, Ragno P (2005) Soluble and cleaved forms of the urokinase-receptor: degradation products or active molecules? Thromb Haemost 93(2):192–198. doi:10.1267/THRO05020192

    PubMed  CAS  Google Scholar 

  9. Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, Maiguel D, Karumanchi SA, Yap HK, Saleem M, Zhang Q, Nikolic B, Chaudhuri A, Daftarian P, Salido E, Torres A, Salifu M, Sarwal MM, Schaefer F, Morath C, Schwenger V, Zeier M, Gupta V, Roth D, Rastaldi MP, Burke G, Ruiz P, Reiser J (2011) Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 17(8):952–960. doi:10.1038/nm.2411

    Article  PubMed  CAS  Google Scholar 

  10. Stewart CE, Sayers I (2009) Characterisation of urokinase plasminogen activator receptor variants in human airway and peripheral cells. BMC Mol Biol 10:75. doi:10.1186/1471-2199-10-75

    Article  PubMed  Google Scholar 

  11. Pyke C, Eriksen J, Solberg H, Nielsen BS, Kristensen P, Lund LR, Dano K (1993) An alternatively spliced variant of mRNA for the human receptor for urokinase plasminogen activator. FEBS Lett 326(1–3):69–74. doi:0014-5793(93)81763-P

    Article  PubMed  CAS  Google Scholar 

  12. Ye S, Goldsmith EJ (2001) Serpins and other covalent protease inhibitors. Curr Opin Struct Biol 11(6):740–745. doi:S0959-440X(01)00275-5

    Article  PubMed  CAS  Google Scholar 

  13. Lijnen HR (2005) Pleiotropic functions of plasminogen activator inhibitor-1. J Thromb Haemost 3(1):35–45. doi:10.1111/j.1538-7836.2004.00827.x

    Article  PubMed  CAS  Google Scholar 

  14. Croucher DR, Saunders DN, Lobov S, Ranson M (2008) Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Nat Rev Cancer 8(7):535–545. doi:10.1038/nrc2400

    Article  PubMed  CAS  Google Scholar 

  15. Laufs S, Schumacher J, Allgayer H (2006) Urokinase-receptor (u-PAR): an essential player in multiple games of cancer: a review on its role in tumor progression, invasion, metastasis, proliferation/dormancy, clinical outcome and minimal residual disease. Cell Cycle 5(16):1760–1771

    Article  PubMed  CAS  Google Scholar 

  16. Ulisse S, Baldini E, Sorrenti S, D’Armiento M (2009) The urokinase plasminogen activator system: a target for anti-cancer therapy. Curr Cancer Drug Targets 9(1):32–71

    Article  PubMed  CAS  Google Scholar 

  17. Xiao W, Hsu YP, Ishizaka A, Kirikae T, Moss RB (2005) Sputum cathelicidin, urokinase plasminogen activation system components, and cytokines discriminate cystic fibrosis, COPD, and asthma inflammation. Chest 128(4):2316–2326. doi:10.1378/chest.128.4.2316

    Article  PubMed  CAS  Google Scholar 

  18. Chu EK, Cheng J, Foley JS, Mecham BH, Owen CA, Haley KJ, Mariani TJ, Kohane IS, Tschumperlin DJ, Drazen JM (2006) Induction of the plasminogen activator system by mechanical stimulation of human bronchial epithelial cells. Am J Respir Cell Mol Biol 35(6):628–638. doi:10.1165/rcmb.2006-0040OC

    Article  PubMed  CAS  Google Scholar 

  19. Stewart CE, Nijmeh HS, Brightling CE, Sayers I (2011) uPAR regulates bronchial epithelial repair in vitro and is elevated in asthmatic epithelium. Thorax 67(6):477–487. doi:10.1136/thoraxjnl-2011-200508

    Article  PubMed  Google Scholar 

  20. Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, Ellwanger A, Sidhu SS, Dao-Pick TP, Pantoja C, Erle DJ, Yamamoto KR, Fahy JV (2007) Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci USA 104(40):15858–15863. doi:10.1073/pnas.0707413104

    Article  PubMed  CAS  Google Scholar 

  21. Wang IM, Stepaniants S, Boie Y, Mortimer JR, Kennedy B, Elliott M, Hayashi S, Loy L, Coulter S, Cervino S, Harris J, Thornton M, Raubertas R, Roberts C, Hogg JC, Crackower M, O’Neill G, Pare PD (2008) Gene expression profiling in patients with chronic obstructive pulmonary disease and lung cancer. Am J Respir Crit Care Med 177(4):402–411. doi:10.1164/rccm.200703-390OC

    Article  PubMed  CAS  Google Scholar 

  22. Harbeck N, Schmitt M, Paepke S, Allgayer H, Kates RE (2007) Tumor-associated proteolytic factors uPA and PAI-1: critical appraisal of their clinical relevance in breast cancer and their integration into decision-support algorithms. Crit Rev Clin Lab Sci 44(2):179–201. doi:10.1080/10408360601040970

    Article  PubMed  CAS  Google Scholar 

  23. Almasi CE, Christensen IJ, Hoyer-Hansen G, Dano K, Pappot H, Dienemann H, Muley T (2011) Urokinase receptor forms in serum from non-small cell lung cancer patients: relation to prognosis. Lung Cancer 74(3):510–515. doi:10.1016/j.lungcan.2011.05.008

    Article  PubMed  Google Scholar 

  24. Yoshino H, Endo Y, Watanabe Y, Sasaki T (1998) Significance of plasminogen activator inhibitor 2 as a prognostic marker in primary lung cancer: association of decreased plasminogen activator inhibitor 2 with lymph node metastasis. Br J Cancer 78(6):833–839

    Article  PubMed  CAS  Google Scholar 

  25. Kirchheimer JC, Wojta J, Christ G, Binder BR (1989) Functional inhibition of endogenously produced urokinase decreases cell proliferation in a human melanoma cell line. Proc Natl Acad Sci USA 86(14):5424–5428

    Article  PubMed  CAS  Google Scholar 

  26. Fischer K, Lutz V, Wilhelm O, Schmitt M, Graeff H, Heiss P, Nishiguchi T, Harbeck N, Kessler H, Luther T, Magdolen V, Reuning U (1998) Urokinase induces proliferation of human ovarian cancer cells: characterization of structural elements required for growth factor function. FEBS Lett 438(1–2):101–105. doi:S0014-5793(98)01279-4

    Article  PubMed  CAS  Google Scholar 

  27. Kanse SM, Benzakour O, Kanthou C, Kost C, Lijnen HR, Preissner KT (1997) Induction of vascular SMC proliferation by urokinase indicates a novel mechanism of action in vasoproliferative disorders. Arterioscler Thromb Vasc Biol 17(11):2848–2854

    Article  PubMed  CAS  Google Scholar 

  28. Yanamandra N, Konduri SD, Mohanam S, Dinh DH, Olivero WC, Gujrati M, Nicolson GL, Obeyeseke M, Rao JS (2000) Downregulation of urokinase-type plasminogen activator receptor (uPAR) induces caspase-mediated cell death in human glioblastoma cells. Clin Exp Metastasis 18(7):611–615

    Article  PubMed  CAS  Google Scholar 

  29. Alfano D, Franco P, Vocca I, Gambi N, Pisa V, Mancini A, Caputi M, Carriero MV, Iaccarino I, Stoppelli MP (2005) The urokinase plasminogen activator and its receptor: role in cell growth and apoptosis. Thromb Haemost 93(2):205–211. doi:10.1267/THRO05020205

    PubMed  CAS  Google Scholar 

  30. Kjoller L (2002) The urokinase plasminogen activator receptor in the regulation of the actin cytoskeleton and cell motility. Biol Chem 383(1):5–19. doi:10.1515/BC.2002.002

    Article  PubMed  CAS  Google Scholar 

  31. Legrand C, Polette M, Tournier JM, de Bentzmann S, Huet E, Monteau M, Birembaut P (2001) uPA/plasmin system-mediated MMP-9 activation is implicated in bronchial epithelial cell migration. Exp Cell Res 264(2):326–336. doi:10.1006/excr.2000.5125

    Article  PubMed  CAS  Google Scholar 

  32. Kwaan HC, Wang J, Svoboda K, Declerck PJ (2000) Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis. Br J Cancer 82(10):1702–1708. doi:10.1054/bjoc.2000.1207

    Article  PubMed  CAS  Google Scholar 

  33. Rossignol P, Ho-Tin-Noe B, Vranckx R, Bouton MC, Meilhac O, Lijnen HR, Guillin MC, Michel JB, Angles-Cano E (2004) Protease nexin-1 inhibits plasminogen activation-induced apoptosis of adherent cells. J Biol Chem 279(11):10346–10356. doi:10.1074/jbc.M310964200M310964200

    Article  PubMed  CAS  Google Scholar 

  34. Chorostowska-Wynimko J, Kedzior M, Struniawski R, Jagus P, Skrzypczak-Jankun E, Jankun J (2010) Cell phenotype determines PAI-1 antiproliferative effect - suppressed proliferation of the lung cancer but not prostate cancer cells. Pneumonol Alergol Pol 78(4):279–283

    PubMed  CAS  Google Scholar 

  35. Providence KM, White LA, Tang J, Gonclaves J, Staiano-Coico L, Higgins PJ (2002) Epithelial monolayer wounding stimulates binding of USF-1 to an E-box motif in the plasminogen activator inhibitor type 1 gene. J Cell Sci 115(Pt 19):3767–3777

    Article  PubMed  CAS  Google Scholar 

  36. Maquerlot F, Galiacy S, Malo M, Guignabert C, Lawrence DA, d’Ortho MP, Barlovatz-Meimon G (2006) Dual role for plasminogen activator inhibitor type 1 as soluble and as matricellular regulator of epithelial alveolar cell wound healing. Am J Pathol 169(5):1624–1632. doi:10.2353/ajpath.2006.051053

    Article  PubMed  CAS  Google Scholar 

  37. Stevens PT, Kicic A, Sutanto EN, Knight DA, Stick SM (2008) Dysregulated repair in asthmatic paediatric airway epithelial cells: the role of plasminogen activator inhibitor-1. Clin Exp Allergy 38(12):1901–1910. doi:10.1111/j.1365-2222.2008.03093.x

    Article  PubMed  CAS  Google Scholar 

  38. Bechtel MJ, Wysocki NS, Heidtmann A, Stark HJ, Fusenig N, Kramer MD, Schaefer BM (1998) Plasminogen activator inhibitor type 2 is expressed in keratinocytes during re-epithelialization of epidermal defects. Br J Dermatol 138(1):22–28

    Article  PubMed  CAS  Google Scholar 

  39. Dickinson JL, Bates EJ, Ferrante A, Antalis TM (1995) Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha-induced apoptosis. Evidence for an alternate biological function. J Biol Chem 270(46):27894–27904

    Article  PubMed  CAS  Google Scholar 

  40. Barton SJ, Koppelman GH, Vonk JM, Browning CA, Nolte IM, Stewart CE, Bainbridge S, Mutch S, Rose-Zerilli MJ, Postma DS, Maniatis N, Henry AP, Hall IP, Holgate ST, Tighe P, Holloway JW, Sayers I (2009) PLAUR polymorphisms are associated with asthma, PLAUR levels, and lung function decline. J Allergy Clin Immunol 123(6):1391–1400 e1317. doi:10.1016/j.jaci.2009.03.014

    Article  PubMed  CAS  Google Scholar 

  41. Stewart CE, Hall IP, Parker SG, Moffat MF, Wardlaw AJ, Connolly MJ, Ruse C, Sayers I (2009) PLAUR polymorphisms and lung function in UK smokers. BMC Med Genet 10:112. doi:10.1186/1471-2350-10-112

    Article  PubMed  Google Scholar 

  42. Ke Y, Reddel RR, Gerwin BI, Miyashita M, McMenamin M, Lechner JF, Harris CC (1988) Human bronchial epithelial cells with integrated SV40 virus T antigen genes retain the ability to undergo squamous differentiation. Differentiation 38(1):60–66

    Article  PubMed  CAS  Google Scholar 

  43. Lieber M, Smith B, Szakal A, Nelson-Rees W, Todaro G (1976) A continuous tumor-cell line from a human lung carcinoma with properties of type II alveolar epithelial cells. Int J Cancer 17(1):62–70

    Article  PubMed  CAS  Google Scholar 

  44. van Leeuwen DM, van Agen E, Gottschalk RW, Vlietinck R, Gielen M, van Herwijnen MH, Maas LM, Kleinjans JC, van Delft JH (2007) Cigarette smoke-induced differential gene expression in blood cells from monozygotic twin pairs. Carcinogenesis 28(3):691–697. doi:10.1093/carcin/bgl199

    Article  PubMed  Google Scholar 

  45. Luther T, Magdolen V, Albrecht S, Kasper M, Riemer C, Kessler H, Graeff H, Muller M, Schmitt M (1997) Epitope-mapped monoclonal antibodies as tools for functional and morphological analyses of the human urokinase receptor in tumor tissue. Am J Pathol 150(4):1231–1244

    PubMed  CAS  Google Scholar 

  46. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63. doi:0022-1759(83)90303-4

    Article  PubMed  CAS  Google Scholar 

  47. Sato S, Kopitz C, Grismayer B, Beaufort N, Reuning U, Schmitt M, Luther T, Kotzsch M, Kruger A, Magdolen V (2011) 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 127(3):649–657. doi:10.1007/s10549-010-1042-5

    Article  PubMed  CAS  Google Scholar 

  48. Ploug M, Rahbek-Nielsen H, Nielsen PF, Roepstorff P, Dano K (1998) Glycosylation profile of a recombinant urokinase-type plasminogen activator receptor expressed in Chinese hamster ovary cells. J Biol Chem 273(22):13933–13943

    Article  PubMed  CAS  Google Scholar 

  49. Shetty S, Padijnayayveetil J, Tucker T, Stankowska D, Idell S (2008) The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability. Am J Physiol Lung Cell Mol Physiol 295(6):L967–L975. doi:10.1152/ajplung.90349.2008

    Article  PubMed  CAS  Google Scholar 

  50. Bhandary YP, Shetty SK, Marudamuthu AS, Gyetko MR, Idell S, Gharaee-Kermani M, Shetty RS, Starcher BC, Shetty S (2012) Regulation of alveolar epithelial cell apoptosis and pulmonary fibrosis by coordinate expression of components of the fibrinolytic system. Am J Physiol Lung Cell Mol Physiol 302(5):L463–L473. doi:10.1152/ajplung.00099.2011

    Article  PubMed  CAS  Google Scholar 

  51. Riittinen L, Limongi P, Crippa MP, Conese M, Hernandez-Marrero L, Fazioli F, Blasi F (1996) Removal of domain D2 or D3 of the human urokinase receptor does not affect ligand affinity. FEBS Lett 381(1–2):1–6. doi:0014-5793(96)00033-6

    Article  PubMed  CAS  Google Scholar 

  52. Degryse B, Resnati M, Czekay RP, Loskutoff DJ, Blasi F (2005) Domain 2 of the urokinase receptor contains an integrin-interacting epitope with intrinsic signaling activity: generation of a new integrin inhibitor. J Biol Chem 280(26):24792–24803. doi:10.1074/jbc.M413954200

    Article  PubMed  CAS  Google Scholar 

  53. Wei Y, Tang CH, Kim Y, Robillard L, Zhang F, Kugler MC, Chapman HA (2007) Urokinase receptors are required for alpha 5 beta 1 integrin-mediated signaling in tumor cells. J Biol Chem 282(6):3929–3939. doi:10.1074/jbc.M607989200

    Article  PubMed  CAS  Google Scholar 

  54. Chaurasia P, Aguirre-Ghiso JA, Liang OD, Gardsvoll H, Ploug M, Ossowski L (2006) A region in urokinase plasminogen receptor domain III controlling a functional association with alpha5beta1 integrin and tumor growth. J Biol Chem 281(21):14852–14863. doi:10.1074/jbc.M512311200

    Article  PubMed  CAS  Google Scholar 

  55. Jo M, Thomas KS, Wu L, Gonias SL (2003) Soluble urokinase-type plasminogen activator receptor inhibits cancer cell growth and invasion by direct urokinase-independent effects on cell signaling. J Biol Chem 278(47):46692–46698. doi:10.1074/jbc.M308808200

    Article  PubMed  CAS  Google Scholar 

  56. Gupta R, Chetty C, Bhoopathi P, Lakka S, Mohanam S, Rao JS, Dinh DE (2011) Downregulation of uPA/uPAR inhibits intermittent hypoxia-induced epithelial-mesenchymal transition (EMT) in DAOY and D283 medulloblastoma cells. Int J Oncol 38(3):733–744. doi:10.3892/ijo.2010.883

    PubMed  CAS  Google Scholar 

  57. Kalogeraki A, Tzardi M, Zoras O, Giannikaki E, Papadakis M, Tamiolakis D, Petraki PE, Diamantis A, Siafakas N, Stathopoulos E (2010) Apoptosis and cell proliferation correlated with tumor grade in patients with lung adenocarcinoma. In Vivo 24(5):667–670

    PubMed  CAS  Google Scholar 

  58. Cohen L, Xueping E, Tarsi J, Ramkumar T, Horiuchi TK, Cochran R, DeMartino S, Schechtman KB, Hussain I, Holtzman MJ, Castro M (2007) Epithelial cell proliferation contributes to airway remodeling in severe asthma. Am J Respir Crit Care Med 176(2):138–145. doi:10.1164/rccm.200607-1062OC

    Article  PubMed  CAS  Google Scholar 

  59. Heijink IH, Brandenburg SM, Noordhoek JA, Postma DS, Slebos DJ, van Oosterhout AJ (2010) Characterisation of cell adhesion in airway epithelial cell types using electric cell-substrate impedance sensing. Eur Respir J 35(4):894–903. doi:10.1183/09031936.00065809

    Article  PubMed  CAS  Google Scholar 

  60. Patnaik SK, Kannisto E, Yendamuri S (2010) Overexpression of microRNA miR-30a or miR-191 in A549 lung cancer or BEAS-2B normal lung cell lines does not alter phenotype. PLoS ONE 5(2):e9219. doi:10.1371/journal.pone.0009219

    Article  PubMed  Google Scholar 

  61. Merolla R, Rebert NA, Tsiviste PT, Hoffmann SP, Panuska JR (1995) Respiratory syncytial virus replication in human lung epithelial cells: inhibition by tumor necrosis factor alpha and interferon beta. Am J Respir Crit Care Med 152(4 Pt 1):1358–1366

    PubMed  CAS  Google Scholar 

  62. Chitra E, Lin YW, Davamani F, Hsiao KN, Sia C, Hsieh SY, Wei OL, Chen JH, Chow YH (2010) Functional interaction between Env oncogene from Jaagsiekte sheep retrovirus and tumor suppressor Sprouty2. Retrovirology 7:62. doi:10.1186/1742-4690-7-62

    Article  PubMed  Google Scholar 

  63. Gueler F, Rong S, Mengel M, Park JK, Kiyan J, Kirsch T, Dumler I, Haller H, Shushakova N (2008) Renal urokinase-type plasminogen activator (uPA) receptor but not uPA deficiency strongly attenuates ischemia reperfusion injury and acute kidney allograft rejection. J Immunol 181(2):1179–1189

    PubMed  CAS  Google Scholar 

  64. Adachi Y, Lakka SS, Chandrasekar N, Yanamandra N, Gondi CS, Mohanam S, Dinh DH, Olivero WC, Gujrati M, Tamiya T, Ohmoto T, Kouraklis G, Aggarwal B, Rao JS (2001) Down-regulation of integrin alpha(v)beta(3) expression and integrin-mediated signaling in glioma cells by adenovirus-mediated transfer of antisense urokinase-type plasminogen activator receptor (uPAR) and sense p16 genes. J Biol Chem 276(50):47171–47177

    Article  PubMed  CAS  Google Scholar 

  65. D’Alessio S, Gerasi L, Blasi F (2008) uPAR-deficient mouse keratinocytes fail to produce EGFR-dependent laminin-5, affecting migration in vivo and in vitro. J Cell Sci 121(Pt 23):3922–3932. doi:10.1242/jcs.037549

    Article  PubMed  Google Scholar 

  66. Liang OD, Chavakis T, Kanse SM, Preissner KT (2001) Ligand binding regions in the receptor for urokinase-type plasminogen activator. J Biol Chem 276(31):28946–28953

    Article  PubMed  CAS  Google Scholar 

  67. Gardsvoll H, Gilquin B, Le Du MH, Menez A, Jorgensen TJ, Ploug M (2006) Characterization of the functional epitope on the urokinase receptor. Complete alanine scanning mutagenesis supplemented by chemical cross-linking. J Biol Chem 281(28):19260–19272. doi:10.1074/jbc.M513583200

    Article  PubMed  CAS  Google Scholar 

  68. Bdeir K, Kuo A, Mazar A, Sachais BS, Xiao W, Gawlak S, Harris S, Higazi AA, Cines DB (2000) A region in domain II of the urokinase receptor required for urokinase binding. J Biol Chem 275(37):28532–28538. doi:10.1074/jbc.M001595200

    Article  PubMed  CAS  Google Scholar 

  69. Li Y, Lawrence DA, Zhang L (2003) Sequences within domain II of the urokinase receptor critical for differential ligand recognition. J Biol Chem 278(32):29925–29932. doi:10.1074/jbc.M300751200

    Article  PubMed  CAS  Google Scholar 

  70. Fazioli F, Resnati M, Sidenius N, Higashimoto Y, Appella E, Blasi F (1997) A urokinase-sensitive region of the human urokinase receptor is responsible for its chemotactic activity. EMBO J 16(24):7279–7286. doi:10.1093/emboj/16.24.7279

    Article  PubMed  CAS  Google Scholar 

  71. Madsen CD, Ferraris GM, Andolfo A, Cunningham O, Sidenius N (2007) uPAR-induced cell adhesion and migration: vitronectin provides the key. J Cell Biol 177(5):927–939. doi:10.1083/jcb.200612058

    Article  PubMed  CAS  Google Scholar 

  72. Gardsvoll H, Ploug M (2007) 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 282(18):13561–13572. doi:10.1074/jbc.M610184200

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Asthma UK grant 08/017 to IS. The authors thank Ben Willson (Molecular and Medical Sciences, University of Nottingham) for setting up the CellProfiler pipeline for wound repair analysis.

Conflict of interest

The author(s) declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Division of Therapeutics and Molecular Medicine, University of Nottingham, Nottingham, NG7 2UH, UK

    Ceri E. Stewart & Ian Sayers

Authors
  1. Ceri E. Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ian Sayers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ian Sayers.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stewart, C.E., Sayers, I. Urokinase Receptor Orchestrates the Plasminogen System in Airway Epithelial Cell Function. Lung 191, 215–225 (2013). https://doi.org/10.1007/s00408-013-9450-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-013-9450-z

Keywords

Search

Navigation