Low density lipoprotein receptor-related protein/α2-macroglobulin receptor is an hepatic receptor for tissue-type plasminogen activator

Guojun Bu, Suzanne Williams, Dudley K. Strickland, Alan L. Schwartz

Research output: Contribution to journalArticlepeer-review

268 Scopus citations

Abstract

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 ≈500 kDa. Another recently identified membrane receptor, low density lipoprotein receptor-related protein/α2-macroglobulin receptor (LRP/α2MR), was also detected on MH1C1 hepatoma cells by using immunoprecipitation with anti-LRP/α2MR antibody. When analyzed by SDS/PAGE, we found the t-PA receptor identified on MH1C1 cells comigrated with the large subunit of LRP/α2MR. The t-PA receptor was immunoprecipitated by an anti-LRP/α2MR 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 α2-macroglobulin could bind to LRP/α2MR simultaneously without competing with one another for binding, suggesting that the two ligands bound to two independent sites on the LRP/α2MR molecule. Furthermore, a 39-kDa protein, which modulates ligand binding to LRP/α2MR, 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/α2MR.

Original languageEnglish (US)
Pages (from-to)7427-7431
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume89
Issue number16
DOIs
StatePublished - 1992

Keywords

  • 39-kDa protein
  • Clearance
  • Endocytosis
  • Hepatocyte

ASJC Scopus subject areas

  • General

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