THE LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEIN ALPHA(2)-MACROGLOBULIN RECEPTOR REGULATES CELL-SURFACE PLASMINOGEN-ACTIVATOR ACTIVITY ON HUMAN TROPHOBLAST CELLS/

The low density lipoprotein receptor-related protein/alpha(2)-macroglo bulin receptor (LRP/alpha(2)MR) mediates the internalization of numero us ligands, including prourokinase (pro-UK) and complexes between two- chain urokinase (tc-u-PA) and plasminogen activator inhibitor type-1 ( PAI-I), It has been suggested that through its ability to internalize these ligands, LRP/alpha(2)MR may regulate the expression of plasminog en activator activity on cell surfaces; this hypothesis, however, has not been experimentally confirmed. To address this issue, we assessed the ability of LRP/alpha(2)MR to regulate plasminogen activator activi ty on human trophoblast cells, which express both LRP/alpha(2)MR and t he urokinase receptor (uPAR). Trophoblasts internalized and degraded e xogenous I-125-pro-UK (primarily following its conversion to tc-u-PA a nd incorporation into tc-u-PA.PAI: complexes) in an LRP/alpha(2)MR-dep endent manner, which was inhibited by the LRP/alpha(2)MR receptor asso ciated protein, Receptor-associated protein also caused a similar to 5 0% reduction in cell surface plasminogen activator activity and delaye d the regeneration of unoccupied uPAR by cells on which uPAR were init ially saturated with pro-UK. Identical effects were caused by anti-LRP /alpha(2)MR antibodies. These results demonstrate that LRP/alpha(2)MR promotes the expression of cell surface plasminogen activator activity on trophoblasts by facilitating the clearance of tc-u-PA.PAI complexe s and regeneration of unoccupied cell surface uPAR.