Extracellular alpha 6 integrin cleavage by urokinase-type plasminogen activator in human prostate cancer.
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.
Demetriou
Manolis C
MC
Department of Cell Biology and Anatomy, University of Arizona, Tucson, AZ 85724, USA.
Pennington
Michael E
ME
Nagle
Raymond B
RB
Cress
Anne E
AE
D000906:Antibodies / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045604:Extracellular Fluid / Q000378:metabolism*; D005341:Fibrinolysin / Q000172:deficiency; D006801:Humans; D039503:Integrin alpha6 / Q000378:metabolism*; D008297:Male; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000906:Antibodies; D002273:Carcinogens; D004791:Enzyme Inhibitors; D039503:Integrin alpha6; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator