The low density lipoprotein receptor-related protein/α2-macroglobulin receptor regulates cell surface plasminogen activator activity on human trophoblast cells

Abstract

The low density lipoprotein receptor-related protein/α2-macroglobulin receptor (LRP/α2MR) mediates the internalization of numerous ligands, including prourokinase (pro-UK) and complexes between two-chain urokinase (tc-u-PA) and plasminogen activator inhibitor type-1 (PAI-1). It has been suggested that through its ability to internalize these ligands, LRP/α2MR may regulate the expression of plasminogen activator activity on cell surfaces; this hypothesis, however, has not been experimentally confirmed. To address this issue, we assessed the ability of LRP/α2MR to regulate plasminogen activator activity on human trophoblast cells, which express both LRP/α2MR and the urokinase receptor (uPAR). Trophoblasts internalized and degraded exogenous 125I-pro-UK (primarily following its conversion to tc- u-PA and incorporation into tc-u-PA·PAI complexes) in an LRP/α2MR- dependent manner, which was inhibited by the LRP/α2MR receptor-associated protein. Receptor-associated protein also caused a ~50% reduction in cell surface plasminogen activator activity and delayed the regeneration of unoccupied uPAR by cells on which uPAR were initially saturated with pro-UK. Identical effects were caused by anti-LRP/α2MR antibodies. These results demonstrate that LRP/α2MR promotes the expression of cell surface plasminogen activator activity on trophoblasts by facilitating the clearance of tc-u-PA·PAI complexes and regeneration of unoccupied cell surface uPAR.