Skip to main content
SpringerLink
Log in
Book cover

Apoptosis, Cell Signaling, and Human Diseases pp 167–179Cite as

Urokinase/Urokinase Receptor-Mediated Signaling in Cancer

  • Chapter

  • 978 Accesses

Summary

Experimental oncogenic transformation or in spontaneous human cancers, mitogenesis and expression of fibrinolytic components such as urokinase (uPA), its receptor (uPAR), and its major inhibitor plasminogen activator inhibtor-1 (PAI-1) or -2 (PAI-2) are activated by common signaling mechanisms. In tumor cells of mesenchymal or epithelial origin uPA, uPAR, and PAIs or metallo-proteinases (MMPs) are overexpressed and these molecules are implicated in tumor invasion or metastasis. Oncogenic stimuli constitutively activate extracellular-regulated kinases (Erk1/2) and NH2-Jun-kinase (Jnk). Tumor or transformed cells typically overexpress uPA and uPAR and show increased activation of the above signaling modules. These signaling intermediaries are involved in the expression of uPA and uPAR as well as mitogenesis, neoplastic growth and metaststic spread and tissue remodeling as occurs in the pathogenesis of neoplasia.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   189.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. New Eng J Med 1986;315(26): 1650–1659.

    Article  PubMed  CAS  Google Scholar 

  2. Ghiso JAA, Alonso DF, Farias Gomez DE, Joffe Deregulation of the signaling pathways controlling urokinase production: its relationship with the invasive phenotype. Eur J Biochem 1999;263:295–304.

    Article  CAS  Google Scholar 

  3. Mazar Henkin J, Goldfarb RH. The urokinase plasminogen activator system in cancer: Implications for tumor angiogenesis and metastasis. Angiogenesis 2000;3:15–32.

    Article  Google Scholar 

  4. Dano K, Behrendt N, Brunner N, Ellis V, Ploug M, Pyke The urokinase receptor: protein Structure and role in plasminogen activation and cancer Invasion. Fibrinolysis 1994;1:189–203.

    Article  Google Scholar 

  5. Shetty S, Kumar A, Johnson A, Idell S. Regulation of mesothelial cell mitogenesis by antisense oligonucleotides for the urokinase receptor. Antisense Res Dev 1995;5:307–314.

    PubMed  CAS  Google Scholar 

  6. Shetty S, Kumar A, Johnson A, Pueblitz S, Idell S. Urokinase receptor in human malignant mesothelioma cells: role in tumor cell mitogenesis and proteolysis. Am J Physiol 1995;268:L972–L982.

    PubMed  CAS  Google Scholar 

  7. Rabbani SA, Gladu J, Mazar 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(2): 137–145.

    Article  PubMed  CAS  Google Scholar 

  8. Xing RH, Mazar A, Henkin J, Rabbani SA. Prevention of breast cancer growth, invasion, and metastasis by antiestrogen tamoxifen alone or in combination with urokinase inhibitor B-428. Cancer Res 1997;57:3585–3593.

    PubMed  CAS  Google Scholar 

  9. Bhat GJ, Gunaje JJ, Idell S. Urokinase-type plasminogen activator induces tyrosine phos-phorylation of a 78-kDa protein in H-157 cells. Am J Physiol 1998;277:L301–L309.

    Google Scholar 

  10. Idell S. Anticoagulants for acute respiratory distress syndrome: Can they work. Am J Resp Crit Care Med 2001;164:517–520.

    PubMed  CAS  Google Scholar 

  11. Alfano D, Franco P, Vocca I, et al. The urokinase plasminogen activator and its receptor: Role in cell growth and apoptosis. Thromb Haemostat 2005;93:205–211.

    CAS  Google Scholar 

  12. Montuori N, Salzano S, Rossi G, Ragno P. Urokinase-type plasminogen activator upregulates the expression of its cellular receptor FEBS Letters 2000;476:166–170.

    Article  PubMed  CAS  Google Scholar 

  13. Shetty S, Idell S. Urokinase induces expression of its own receptor in Beas2B lung epithelial cells. J Biol Chem 2001;276:24,549-24,556.

    Article  Google Scholar 

  14. Shetty S, Pendurthi UR, Halady PKS, Azghani AO, Idell S. Urokinase induces its own expression in Beas2B lung epithelial cells. Am J Physiol (Lung Cell Mol Physiol) 2002; 283:L319–L328.

    CAS  Google Scholar 

  15. Shetty S, Bdeir K, Cines DB, Idell S. Induction of plasminogen activator inhibitor-1 by urokinase in lung epithelial cells. J Biol Chem 2003;278(20): 18,124-18,131.

    Article  CAS  Google Scholar 

  16. Shetty S, Muniyappa H, Halady PK, Idell S. Regulation of urokinase receptor expression by phosphoglycerate kinase. Am J Resp Cell Mol Biol 2004;31(1): 100–106.

    Article  CAS  Google Scholar 

  17. Shetty S, Idell S. Urokinase receptor mRNA stability involves tyrosine phosphorylation in lung epithelial cells. Am J Resp Cell Mol Biol 2004;30(1):69–75.

    Article  CAS  Google Scholar 

  18. Shetty S, Idell S. Post-transcriptional regulation of urokinase mRNA: Identification of a novel urokinase mRNA-binding protein in human lung epithelial cells in vitro. J Biol Chem 2000;275(18):13,771-13,779.

    Article  Google Scholar 

  19. Shetty S. Regulation of Urokinase Receptor mRNA Stability by hnRNPC in Lung Epithelial Cells. Mol Cell Biochem 2005;272:107–118.

    Article  PubMed  CAS  Google Scholar 

  20. Shetty S, Idell S. Posttranscriptional regulation of plasminogen activator inhibitor-1 in human lung carcinoma cells in vitro. Am J Physiol-Lung Cell Mol Physiol 2000;278(1):L148–L156.

    PubMed  CAS  Google Scholar 

  21. Shetty S, Kumar A, Idell S. Posttranscriptional regulation of urokinase receptor mRNA: identification of a novel urokinase receptor mRNA binding protein in human mesothelioma cells. Mol Cell Biol 1997;17(3): 1075–1083.

    PubMed  CAS  Google Scholar 

  22. Tran H, Maurer F, Nagamine Y. Stabilization of urokinase and urokinase receptor mRNAs by HuR is linked to its cytoplasmic accumulation induced by activated mitogen-activated protein kinase-activated protein kinase 2. Mol Cell Biol 2003;23(20):7177–7188.

    Article  PubMed  CAS  Google Scholar 

  23. Montero L, Nagamine Y. Regulation by p38 mitogen-activated protein kinase of adenylate-and uridylate-rich element-mediated urokinase-type plasminogen activator (uPA) messenger RNA stability and uPA-dependent in vitro cell invasion. Cancer Res 1999;59(20): 5286–5293.

    PubMed  CAS  Google Scholar 

  24. Nanbu R, Menoud PA, Nagamine Y. Multiple instability-regulating sites in the 3? untranslated region of the urokinase-type plasminogen activator mRNA. Mol Cell Biol 1994;14(7): 4920–4928.

    PubMed  CAS  Google Scholar 

  25. Heaton JH, Dlakic WM, Gelehrter TD. Posttranscriptional regulation of PAI-1 gene expression. Thromb Haemost 2003;89(6):959–966.

    PubMed  CAS  Google Scholar 

  26. Heaton JH, Dlakic WM, Dlakic M, Gelehrter TD. Identification and cDNA cloning of a novel RNA-binding protein that interacts with the cyclic nucleotide-responsive sequence in the Type-1 plasminogen activator inhibitor mRNA. J Biol Chem 2001;276(5):3341–3347.

    Article  PubMed  CAS  Google Scholar 

  27. Heaton JH, Tillmann-Bogush M, Leff NS, Gelehrter TD. Cyclic nucleotide regulation of type-1 plasminogen activator-inhibitor mRNA stability in rat hepatoma cells. Identification of cis-acting sequences. J Biol Chem 1998;273(23): 14,261-14,268.

    Article  Google Scholar 

  28. Yu H, Stasinopoulos S, Leedman P, Medcalf RL. Inherent instability of plasminogen activator inhibitor type 2 mRNA is regulated by tristetraprolin. J Biol Chem 2003; 278(16):13,912-13,918.

    Article  CAS  Google Scholar 

  29. Tierney MJ, Medcalf RL. Plasminogen activator inhibitor type 2 contains mRNA instability elements within exon 4 of the coding region. Sequence homology to coding region instability determinants in other mRNAs. J Biol Chem 2001;276(17): 13,675-13,684.

    Google Scholar 

  30. Maurer F, Tierney M, Medcalf RL. An AU-rich sequence in the 3?-UTR of plasminogen activator inhibitor type 2 (PAI-2) mRNA promotes PAI-2 mRNA decay and provides a binding site for nuclear HuR. Nuc Acid Res 1999;27(7): 1664–1673.

    Article  CAS  Google Scholar 

  31. Carlin SM, Resink TJ, Tamm M, Roth M. Urokinase signal transduction and its role in cell migration. FASEB J 2005;19:195–202.

    Article  PubMed  CAS  Google Scholar 

  32. 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.

    Article  PubMed  CAS  Google Scholar 

  33. Ossowski L, Auguirre-Ghiso JA. Urokinase receptor and integrin partnership: Coordination of signaling for cell adhesion, migration and growth. Curr Opin Cell Biol 2000;12:613–620.

    Article  PubMed  CAS  Google Scholar 

  34. Dulmer I, Weis A, Mayboroda OA, et al. The Jak/Stat pathway and urokinase receptor sig-naling in human aortic vascular smooth muscle cells. J Biol Chem 1998;273:315–321.

    Article  Google Scholar 

  35. Koshelnick Y, Ehart M, Hufnag P, Heinrich PC, Binder BR. 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;272:28,563-28,567.

    Article  Google Scholar 

  36. Dumler I, Petri T, Schleuning WD. Induction of c-fos gene expression by urokinase-type plasminogen activator in human ovarian cancer cells. FEBS Letter 1994;343:103–106.

    Article  CAS  Google Scholar 

  37. Kunigal S, Kusch A, Tkachuk N, et al. Monocyte-expressed urokinase inhibits vascular smooth muscle cell growth by activating Stat1. Blood 2003;102:4377–4383.

    Article  PubMed  CAS  Google Scholar 

  38. Shetty S, Gyetko MR, Mazar Induction of p53 by urokinase in lung epithelial cells. J Biol Chem 2005;280:28,133-28,141.

    Article  CAS  Google Scholar 

  39. Lin J, Jin X, Rothman K, Lin H, Tang H, Burke W. Modulation of signal transducer and activator of transcription 3 activities by p53 tumor suppressor in breast cancer cells. Cancer Res 2002;62:376–380.

    PubMed  CAS  Google Scholar 

  40. Berclaz G, Altermatt HJ, Rohrbach V, Siragusa A, Dreher E, Smith PD. EGFR dependent expression of Stat3 but not Stat1 in breast cancer. Int J Oncol 2001;19(6):1155–1160.

    PubMed  CAS  Google Scholar 

  41. Jo M, Thomas KS, O’Donnell DM, Gonias SL. Epidermal growth factor receptor dependent and—independent cell signaling pathways originating from the urokinase receptor. J Biol Chem 2003;278:1642–1646.

    Article  PubMed  CAS  Google Scholar 

  42. Liu D, Auguirre-Ghiso JA, Estrada Y, Ossowski L. EGFR is a tranducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell 2002; 1:445–457.

    Article  PubMed  CAS  Google Scholar 

  43. Aguirre-Ghiso JA, Liu D, Mignatti A, Kovalski K, Ossowski L. 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(4):863–879.

    PubMed  CAS  Google Scholar 

  44. Ghiso JAA. Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo. Oncogene 2002;21(16):2513–2524.

    Article  CAS  Google Scholar 

  45. Bohuslav J, Horejsi V, Hansmann C, et al. Urokinase plasminogen activator receptor, beta 2-integrins, and Src-kinases within a single receptor complex of human monocytes. J Exptl Med 1995;181(4):1381–1390.

    Article  CAS  Google Scholar 

  46. Chandrasekar N, Mohanam S, Gujrati M, Olivero WC, Dinh DH, Rao JS. Down regulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells. Oncogene 2003; 22(3):392–400.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Texas Lung Injury Institute, The University of Texas Health Center at Tyler, Tyler, TX

    Sreerama Shetty & Steven Idell

Authors
  1. Sreerama Shetty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steven Idell
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Biochemistry, University of Texas Health Center at Tyler, Tyler, TX

    Rakesh Srivastava

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Shetty, S., Idell, S. (2006). Urokinase/Urokinase Receptor-Mediated Signaling in Cancer. In: Srivastava, R. (eds) Apoptosis, Cell Signaling, and Human Diseases. Humana Press. https://doi.org/10.1007/978-1-59745-199-4_8

Download citation

Publish with us

Policies and ethics

Search

Navigation