Glycosyl Phosphatidylinositol Anchorage of Tissue Factor Pathway Inhibitor

Zhang, Jing; Piro, Orlando; Lu, Lan; Broze, George J.

doi:10.1161/01.cir.0000078642.45127.7b

Cited by 99 publications

(163 citation statements)

References 21 publications

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“…17 Human TFPI␣ protein has been identified in endothelial cell culture media and purified from HepG2 cells and plasma, 13,18,19 but human TFPI␤ protein has previously only been identified indirectly in ECV304 cells. 6,15,17 A substantial fraction of the TFPI produced by endothelial cells remains at the cell surface and associated with caveolae. 16,20 Phosphatidylinositol-specific phospholipase C (PIPLC) treatment, which cleaves GPI-anchored proteins, releases approximately 80% of cell surface TFPI, and the remaining TFPI can be removed by heparin treatment.…”

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confidence: 99%

TFPIβ is the GPI-anchored TFPI isoform on human endothelial cells and placental microsomes

Girard

Tuley

Broze

2012

Blood

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native C-terminus that directs the attachment of a glycosylphosphatidylinositol (GPI) anchor, but whether TFPI␤ protein is actually expressed is not clear. Moreover, previous studies have suggested that the predominant form of TFPI released from cells by phosphatidylinositolspecific phospholipase C (PIPLC) treatment is TFPI␣, implying it is bound at cell surfaces to a separate GPI-anchored coreceptor. Our studies show that the form of TFPI released by PIPLC treatment of cultured endothelial cells and placental microsomes is actually TFPI␤ based on (1) migration on SDS-PAGE before and after deglycosylation, (2) the lack of a Kunitz-3 domain, and ( IntroductionTissue factor pathway inhibitor (TFPI) is the key endogenous regulator of TF-initiated coagulation. TFPI inhibits factor Xa (FXa) directly, and, in a FXa-dependent manner, inhibits factor VIIa/tissue factor (FVIIa/ TF) activity. 1 The human TFPI gene encodes for 2 dominant messages that are generated by alternative intron/exon splicing (GenBank NM_006287.4, GenBank NM_001032281.2). TFPI␣, the originally described message, encodes a signal peptide that is removed by processing, followed by a 276-amino acid protein that consists of an acidic N-terminal region, 3 tandem Kunitz-type protease inhibitor domains, and a basic C-terminal region. 2 Functional studies reveal that the Kunitz-2 domain mediates binding to and inhibition of FXa, whereas the Kunitz-1 domain is responsible for recognition and inhibition of the TF/FVIIa complex. 3 The Kunitz-3 domain lacks protease inhibitor activity; however, it and the C-terminal basic region of TFPI␣ are required for protein S enhancement of inhibition of FXa. 4,5 The TFPI␤ message lacks the Kunitz-3 and C-terminal exons of TFPI␣, and in their place is an exon that encodes a 42-amino acid C-terminal sequence following residue 181 of TFPI␣. This new C-terminal sequence is predicted to direct the proteolytic cleavage of the peptide following N193 with the attachment of a GPI anchor. The protein mass of TFPI␤ is less than that of TFPI␣, but it migrates on SDS-PAGE at a molecular weight similar to TFPI␣ (46 kDa) apparently because of greater sialylation of its O-linked carbohydrate. 6 In humans, TFPI circulates in plasma at approximately 70 ng/mL (1.6nM), with 80% being a C-terminal truncated form that is lipoprotein associated and the remaining 20% being full-length and near full-length TFPI␣ forms. 7,8 Platelets contain TFPI␣ and, at the site of injury TFPI␣ levels, increase dramatically. 9,10 The parenteral administration of heparin to humans increases the circulating levels of total TFPI in plasma to approximately 2.5-fold baseline levels. 11,12 The form of TFPI that is released is full-length TFPI␣. 13 Heparin also increases the release of TFPI from endothelial cells in culture, 6,14 even though treatment with heparin does not perceptibly reduce surface TFPI. 6,15,16 The endothelium appears to be the major source of TFPI in vivo. In human endothelial cell cultures, the ratio of TFPI␣/TFPI␤ mRNA varies between 5 and 10. 1...

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TFPIβ is the GPI-anchored TFPI isoform on human endothelial cells and placental microsomes

Girard

Tuley

Broze

2012

Blood

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“…However, the procoagulant activity of TF is regulated at multiple levels, including rapid feedback inhibition by TF pathway inhibitor (10) that directs TF to low density microdomains (11). A relatively small portion of total cellular TF is sufficient for procoagulant activity, and various amounts of noncoagulant or cryptic cell surface TF are present dependent on cell type, cellular differentiation, and proliferation (8,12,13).…”

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Tissue Factor Coagulant Function Is Enhanced by Protein-disulfide Isomerase Independent of Oxidoreductase Activity

Versteeg

Ruf

2007

Journal of Biological Chemistry

109

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Protein-disulfide isomerase (PDI) switches tissue factor (TF) from coagulation to signaling by targeting the allosteric Cys 186 -Cys 209 disulfide. Here, we further characterize the interaction of purified PDI with TF. We find that PDI enhances factor VIIadependent substrate factor X activation 5-10-fold in the presence of wild-type, oxidized soluble TF but not TF mutants that contain an unpaired Cys 186 or Cys 209 . PDI-accelerated factor Xa generation was blocked by bacitracin but not influenced by inhibition of vicinal thiols, reduction of PDI, changes in redox gradients, or covalent thiol modification of reduced PDI by N-ethylmaleimide or methyl-methanethiosulfonate, which abolished PDI oxidoreductase but not chaperone activity. PDI had no effect on fully active TF on either negatively charged phospholipids or in activating detergent, indicating that PDI selectively acts upon cryptic TF to facilitate ternary complex formation and macromolecular substrate turnover. PDI activation was reduced upon mutation of TF residues in proximity to the macromolecular substrate binding site, consistent with a primary interaction of PDI with TF. PDI enhanced TF coagulant activity on microvesicles shed from cells, suggesting that PDI plays a role as an activating chaperone for circulating cryptic TF.

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“…TFPIβ is an alternatively spliced form that does not contain the third Kunitz domain and has an alternative carboxyl terminus and has been identified in mice and humans. In vitro, endothelial cells express TFPIβ at a ratio of 0.1 to 0.2 to that of TFPI (8). TFPIβ contains a direct GPI anchor not present in TFPIα TFPIα binds the cell surface through a yet to be identified indirect GPI anchor and binds to endothelial glycosaminoglycans via its carboxyl terminus.…”

Section: Tfpi Structure and Functionmentioning

confidence: 99%

Tissue factor pathway inhibitor as a multifunctional mediator of vascular structure

Simari¹

2012

Front Biosci

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Tissue factor pathway inhibitor (TFPI) is a potent regulator of tissue factor -factor VII-dependent activation of the tissue factor pathway. TFPI is a serine protease inhibitor that contains three Kunitz domains and a basic carboxyl terminus. TFPI is primarily expressed on endothelial cells, and murine models have demonstrated that its expression regulates vascular thrombosis. The localization of TFPI expression and the requirement for TFPI in development suggest a potential role in regulating vascular structure. Data from animal studies suggest that vascular expression of TFPI inhibits pathologic vascular remodeling and inhibits angiogenesis. The mechanism for these effects is diverse and includes tissue factor and factor Xa-dependent and -independent mechanisms. KeywordsTissue factor; atherosclerosis; angiogenesis INTRODUCTIONThe vascular endothelium is a multimodal organ system that provides an integrating focus for the regulation of vascular structure and function. (1) Endothelial-derived nitric oxide would serve as a paradigm for this principle, functionally acting acutely to locally vasodilate vessels but also chronically on the underlying tunica media to affect both vascular structure and function. Other endothelial-derived molecules demonstrate similar multimodal properties. As the interface with blood, the endothelium is exposed to circulating factors and cells, as well as physical forces, which regulate thrombosis. The endothelium integrates proand anti-thrombotic signals to regulate local thrombogenicity. Endothelial cells express tissue factor pathway inhibitor (TFPI), a serine protease inhibitor which is the primary inhibitor of tissue factor (TF)-mediated coagulation. The functionality of TFPI however extends beyond this anticoagulant role, to regulate different aspects of vascular biology. This review will highlight human and experimental data which suggest that TFPI regulates macro and microvessel structure in a diverse manner.Address for correspondence: Robert D. Simari, M.D., Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA, simari.robert@mayo.edu. This is an, un-copyedited, author manuscript that has been accepted for publication in the Frontiers in Bioscience, http:// www.bioscience.org/2012/V4e/af/386/fulltext.htm. This article may not be duplicated or reproduced, other than for personal use or within the rule of "Fair Use of Copyrighted Materials" (section 107, Title 17, U.S. Code) without permission of the copyright holder, the Frontiers in Bioscience. From the time of acceptance following peer review, the full final copy edited article of this manuscript will be made available at http://www.bioscience.org/. The Frontiers in Bioscience disclaims any responsibility or liability for errors or omissions in this version of the un-copyedited manuscript or in any version derived from it by the National Institutes of Health or other parties." NIH Public Access Author ManuscriptFront Biosci (Elite Ed). Author manuscript; available in PMC 201...

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Glycosyl Phosphatidylinositol Anchorage of Tissue Factor Pathway Inhibitor

Cited by 99 publications

References 21 publications

TFPIβ is the GPI-anchored TFPI isoform on human endothelial cells and placental microsomes

TFPIβ is the GPI-anchored TFPI isoform on human endothelial cells and placental microsomes

Tissue Factor Coagulant Function Is Enhanced by Protein-disulfide Isomerase Independent of Oxidoreductase Activity

Tissue factor pathway inhibitor as a multifunctional mediator of vascular structure

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