Low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor is an hepatic receptor for tissue-type plasminogen activator

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 89; no. 16; pp. 7427 - 7431
• Main Authors: Bu, G, Williams, S, Strickland, D K, Schwartz, A L
• Format: Journal Article
• Language: English
• Published: United States National Acad Sciences 15.08.1992
• Subjects: Animals; Antibodies; Cross Reactions; Cross-Linking Reagents; Kinetics; Ligands; Liver Neoplasms, Experimental - metabolism; Low Density Lipoprotein Receptor-Related Protein-1; Rats; Receptors, Immunologic - isolation & purification; Receptors, Immunologic - metabolism; Succinimides; Tissue Plasminogen Activator - isolation & purification; Tissue Plasminogen Activator - metabolism; Tumor Cells, Cultured
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.89.16.7427

Tissue-type plasminogen activator (t-PA), a serine protease that catalyzes the initial and rate-limiting step in the fibrinolytic cascade, is cleared rapidly in vivo by the liver. Using chemical crosslinking, we have recently identified a plasminogen-activator inhibitor type 1 (PAI-1)-independent t-PA clearance receptor on rat hepatoma MH1C1 cells with a relative molecular mass of approximately 500 kDa. Another recently identified membrane receptor, low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP/alpha 2MR), was also detected on MH1C1 hepatoma cells by using immunoprecipitation with anti-LRP/alpha 2MR antibody. When analyzed by SDS/PAGE, we found the t-PA receptor identified on MH1C1 cells comigrated with the large subunit of LRP/alpha 2MR. The t-PA receptor was immunoprecipitated by an anti-LRP/alpha 2MR antibody after chemical crosslinking of specifically bound 125I-labeled t-PA to its receptor. Through chemical crosslinking studies, we found that t-PA and methylamine-activated alpha 2-macroglobulin could bind to LRP/alpha 2MR simultaneously without competing with one another for binding, suggesting that the two ligands bound to two independent sites on the LRP/alpha 2MR molecule. Furthermore, a 39-kDa protein, which modulates ligand binding to LRP/alpha 2MR, was also found to inhibit t-PA binding to its receptor. These data thus show that the t-PA clearance receptor identified on MH1C1 hepatoma cells is LRP/alpha 2MR.