title: Extracellular alpha 6 integrin cleavage by urokinase-type plasminogen activator in human prostate cancer.
abstract: 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.
authors.affiliation: Department of Cell Biology and Anatomy, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Manolis C
authors.initials: MC
authors.lastname: Demetriou
authors.forename: Michael E
authors.initials: ME
authors.lastname: Pennington
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Nagle
authors.forename: Anne E
authors.initials: AE
authors.lastname: Cress
mesh_terms: 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*
chemical_list: D000906:Antibodies; D002273:Carcinogens; D004791:Enzyme Inhibitors; D039503:Integrin alpha6; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator