© 2000 American Heart Association, Inc.
Thrombosis |
Reversible Regulation of Tissue Factor–Induced Coagulation by Glycosyl Phosphatidylinositol–Anchored Tissue Factor Pathway Inhibitor
From the Departments of Immunology (B.M.M., W.R.), Molecular and Experimental Medicine (M.J.H.), and Vascular Biology (M.J.H., B.M.M., W.R.), The Scripps Research Institute, La Jolla, Calif; Deutsches Herzzentrum (I.O.), Munich, Germany; the Department of Pathology (Y.M.) and the Kihara Institute for Biological Research (K.M.), Yokohama City University, Yokohama, Japan; and the Department of Biochemistry (L.V.M.R.), University of Texas Health Center at Tyler, Tyler, Tex.
Correspondence to Dr Wolfram Ruf, Department of Immunology, IMM-17, The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA 92037. E-mail ruf{at}scripps.edu
Abstract—Endothelial and tumor cells synthesize tissue factor pathway inhibitor (TFPI-1), which regulates tissue factor (TF) function by TF · VIIa · Xa · TFPI-1 quaternary complex formation (where VIIa and Xa are coagulation factors) and by translocation of these complexes into glycosphingolipid-rich microdomains of the cell membrane. Recombinant TFPI-1 added exogenously to cells is targeted to a degradation pathway. This study analyzes whether quaternary complex formation with endogenous TFPI-1 results also in internalization and degradation. We demonstrate that endogenous TFPI-1 and recombinant TFPI-1 differ in their distribution on the cell surface. Recombinant TFPI-1 is found in phospholipid- and glycosphingolipid-rich membrane domains, whereas endogenous TFPI-1 preferentially localizes to glycosphingolipid-rich microdomains. On quaternary complex formation, endogenous TFPI-1 remains protease sensitive and accessible for antibodies on intact cells, demonstrating that it is not appreciably internalized. Rather, regulation of TF by TFPI-1 is restored within 12 hours, consistent with dissociation of quaternary complexes on the cell surface. Endogenous TFPI-1 can be released from the cell surface by phospholipase treatment, indicating that TFPI-1 either is a glycosyl phosphatidylinositol (GPI)-anchored protein or binds to a GPI-linked receptor. We demonstrate that expression of a recombinant GPI-anchored form of TFPI-1 targets TF · VIIa complexes to glycosphingolipid-rich membrane fractions. Thus, GPI anchoring of TFPI-1 is sufficient for regulation of TF · VIIa complex function by a pathway of reversible inhibition rather than internalization and degradation.
Key Words: coagulation cascade • Kunitz-type inhibitors • cell surface proteoglycans • glycosphingolipid-rich microdomains
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