Extracellular alpha 6 integrin cleavage by urokinase-type plasminogen activator in human prostate cancer

Exp Cell Res. 2004 Apr 1;294(2):550-8. doi: 10.1016/j.yexcr.2003.11.023.


During human prostate cancer progression, the integrin alpha6beta1 (laminin receptor) is expressed on the cancer cell surface during invasion and in lymph node metastases. We previously identified a novel structural variant of the alpha6 integrin called alpha6p. This variant was produced on the cell surface and was missing the beta-barrel extracellular domain. Using several different concentrations of amiloride, aminobenzamidine and PAI-1 and the urokinase-type plasminogen activator (uPA) function-blocking antibody (3689), we showed that uPA, acting as a protease, is responsible for production of alpha6p. We also showed that addition of uPA in the culture media of cells that do not produce alpha6p, resulted in a dose-dependent alpha6p production. In contrast, the addition of uPA did not result in the cleavage of other integrins. Using alpha2-antiplasmin and plasmin depleted media, we observed that uPA cleaves the alpha6 integrin directly. Further, 12-o-tetradecanoyl-phorbol-13-acetate (TPA) induced the production of alpha6p, and this induction was abolished by PAI-1 but not alpha2-antiplasmin. Finally, the alpha6p integrin variant was detected in invasive human prostate carcinoma tissue indicating that this is not a tissue culture phenomenon. These data, taken together, suggest that this is a novel function of uPA, that is, to remove the beta-barrel ligand-binding domain of the integrin while preserving its heterodimer association.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies / pharmacology
  • Carcinogens / pharmacology
  • Carcinoma / genetics
  • Carcinoma / metabolism*
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Dimerization
  • Enzyme Inhibitors / pharmacology
  • Extracellular Fluid / metabolism*
  • Fibrinolysin / deficiency
  • Humans
  • Integrin alpha6 / metabolism*
  • Male
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Protein Binding / physiology
  • Protein Structure, Tertiary / physiology
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors
  • Urokinase-Type Plasminogen Activator / metabolism*


  • Antibodies
  • Carcinogens
  • Enzyme Inhibitors
  • Integrin alpha6
  • Fibrinolysin
  • Urokinase-Type Plasminogen Activator