Down-regulation of monocyte tissue factor mediated by tissue factor pathway inhibitor and the low density lipoprotein receptor-related protein

Anne Hamik, Hendra Setiadi, Guojun D Bu, Rodger P. McEver, James H. Morrissey

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Inflammatory mediators like bacterial lipopolysaccharide induce monocytes to express tissue factor (TF), the cell-surface protein that triggers the blood clotting cascade in hemostasis and thrombotic disease. The physiologic ligand for TF is the serine protease, factor VIIa (FVIIa), and the resulting bimolecular enzyme, TF/FVIIa, can be reversibly inhibited by tissue factor pathway inhibitor (TFPI). Culturing monocytic cells in the presence of both FVIIa and TFPI caused down-regulation of TF expression via reducing its half-life. To exert this effect, FVIIa had to be competent to bind both TF and TFPI, and TFPI had to contain the C-terminal domain required for binding to other cell-surface receptors, including the low density lipoprotein receptor-related protein (LRP). TF down-regulation by FVIIa plus TFPI was abrogated by the 39-kDa receptor-associated protein, which blocks binding of all known ligands to LRP. Furthermore, treatment with FVIIa plus TFPI caused monocyte TF to colocalize with α-adaptin, a component of clathrin-coated pits. Thus, in addition to reversibly inhibiting TF/FVIIa catalytic activity, TFPI also mediates the permanent down-regulation of cell- surface TF in monocytic cells via LRP-dependent internalization and degradation. This represents an unusual mechanism for receptor internalization, requiring ligand-dependent bridging of one cell-surface receptor (TF) to a second cell-surface receptor (LRP), the latter being capable of clathrin-mediated internalization.

Original languageEnglish (US)
Pages (from-to)4962-4969
Number of pages8
JournalJournal of Biological Chemistry
Volume274
Issue number8
DOIs
StatePublished - Feb 19 1999
Externally publishedYes

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LDL-Receptor Related Proteins
LDL Receptors
Thromboplastin
Factor VIIa
Monocytes
Down-Regulation
Lipoprotein Receptors
Proteins
Cell Surface Receptors
Clathrin
Ligands
LDL-Receptor Related Protein-Associated Protein
lipoprotein-associated coagulation inhibitor
Serine Proteases
Blood Coagulation
Hemostasis
Half-Life
Lipopolysaccharides
Catalyst activity
Membrane Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Down-regulation of monocyte tissue factor mediated by tissue factor pathway inhibitor and the low density lipoprotein receptor-related protein. / Hamik, Anne; Setiadi, Hendra; Bu, Guojun D; McEver, Rodger P.; Morrissey, James H.

In: Journal of Biological Chemistry, Vol. 274, No. 8, 19.02.1999, p. 4962-4969.

Research output: Contribution to journalArticle

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