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.