The low density lipoprotein receptor-related protein mediates the cellular degradation of tissue factor pathway inhibitor

Ilka Warshawsky, George J. Broze, Alan L. Schwartz

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

The low density lipoprotein receptor-related protein/α2-macroglobulin receptor (LRP) is a cell-surface glycoprotein of 4525 amino acids that functions as a hepatic endocytosis receptor for several plasma proteins. These include α2-macroglobulin-protease complexes, free plasminogen activators as well as plasminogen activators complexed with their inhibitors, and β-migrating very low density lipoproteins complexed with either apolipoprotein E or lipoprotein lipase. In the current study we used human and rat hepatoma cell lines to demonstrate that LRP can mediate the degradation of tissue factor pathway inhibitor (TFPI), a Kunitz-type plasma serine protease inhibitor that regulates tissue factor-induced blood coagulation. The cellular degradation of 125I-labeled TFPI (125I-TFPI) was inhibited more than 80% both by antibodies directed against LRP and by the LRP-associated 39-kDa protein, a protein that inhibits the binding and/or cell-mediated degradation of all ligands by LRP. Using rat hepatoma cells, we report that at 4°C, 125I-TFPI binds to approximately 2 x 106 sites per cell with an equilibrium dissociation constant of ≃30 nM. 125I-TFPI binding to the cell surface is not inhibited by the 39-kDa protein. Taken together, our results suggest that TFPI binds to an as-yet-unidentified cell surface molecule. After binding, LRP mediates the cellular degradation of TFPI.

Original languageEnglish
Pages (from-to)6664-6668
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number14
DOIs
StatePublished - Jul 5 1994

Fingerprint

Dive into the research topics of 'The low density lipoprotein receptor-related protein mediates the cellular degradation of tissue factor pathway inhibitor'. Together they form a unique fingerprint.

Cite this