title: The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor regulates cell surface plasminogen activator activity on human trophoblast cells.
abstract: The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor (LRP/alpha2MR) 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/alpha2MR 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/alpha2MR to regulate plasminogen activator activity on human trophoblast cells, which express both LRP/alpha2MR 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/alpha2MR-dependent manner, which was inhibited by the LRP/alpha2MR receptor-associated protein. Receptor-associated protein also caused a approximately 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/alpha2MR antibodies. These results demonstrate that LRP/alpha2MR 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.
authors.affiliation: Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Sakthivel
authors.forename: D
authors.initials: D
authors.lastname: Kniss
authors.forename: C H
authors.initials: CH
authors.lastname: Graham
authors.forename: D K
authors.initials: DK
authors.lastname: Strickland
authors.forename: K R
authors.initials: KR
authors.lastname: McCrae
mesh_terms: D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D015193:Chorionic Villi Sampling; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism
chemical_list: D026503:Low Density Lipoprotein Receptor-Related Protein-1; C524898:PLAUR protein, human; D017395:Plasminogen Activator Inhibitor 1; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase; D020123:Sirolimus