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 MH 1 C 1 cells with a relative molecular mass of ≈500 kDa. Another recently identified membrane receptor, low density lipoprotein receptor-related protein/α 2 -macroglobulin receptor (LRP/α 2 MR), was also detected on MH 1 C 1 hepatoma cells by using immunoprecipitation with anti-LRP/α 2 MR antibody. When analyzed by SDS/PAGE, we found the t-PA receptor identified on MH 1 C 1 cells comigrated with the large subunit of LRP/α 2 MR. The t-PA receptor was immunoprecipitated by an anti-LRP/α 2 MR antibody after chemical crosslinking of specifically bound 125 I-labeled t-PA to its receptor. Through chemical crosslinking studies, we found that t-PA and methylamine-activated α 2 -macroglobulin could bind to LRP/α 2 MR simultaneously without competing with one another for binding, suggesting that the two ligands bound to two independent sites on the LRP/α 2 MR molecule. Furthermore, a 39-kDa protein, which modulates ligand binding to LRP/α 2 MR, was also found to inhibit t-PA binding to its receptor. These data thus show that the t-PA clearance receptor identified on MH 1 C 1 hepatoma cells is LRP/α 2 MR.
Bu, G., Williams, S., Strickland, D. K., & Schwartz, A. L. (2006). Low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor is an hepatic receptor for tissue-type plasminogen activator. Proceedings of the National Academy of Sciences, 89(16), 7427–7431. https://doi.org/10.1073/pnas.89.16.7427