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Blood, 1 December 2007, Vol. 110, No. 12, pp. 3822-3823. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Morrissey, J. H. Search for Related Content PubMed Articles by Morrissey, J. H. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS Comment on Pendurthi et al, page 3900 Encryption remains cryptic James H. Morrissey UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN This study challenges a recent proposal that disulfide bond isomerization switches cell-surface tissue factor between encrypted (non-coagulant) and decrypted (procoagulant) states. Blood clotting is initiated when factor VIIa binds to the integral membrane protein, tissue factor. Curiously, most tissue factor on the surface of resting cells exists in an "encrypted" state with very little clotting activity.1 Damaging the plasma membrane, treating cells with calcium ionophore, or inducing apoptosis all dramatically increase tissue factor activity ("decryption"). Most clotting enzymes are active only when assembled on membranes containing anionic phospholipids (especially phosphatidylserine). Cells actively sequester phosphatidylserine to the inner leaflet of the plasma membrane, but this membrane asymmetry is abolished by agents known to induce tissue factor decryption. The most straightforward explanation for tissue factor decryption is therefore phosphatidylserine exposure, although decryption may also involve tissue factor dimerization and/or localization to membrane rafts.1 A new hypothesis for tissue factor encryption was recently proposed in which a critical disulfide bond (Cys186-Cys209) is disrupted in encrypted tissue factor.2,3 Protein disulfide isomerase (PDI), a protein normally resident in the endoplasmic reticulum, was proposed to control the formation of this critical disulfide on cell-surface tissue factor in a mechanism that neatly explains many facets of tissue factor biology. In addition to triggering clotting, the factor VIIa-tissue factor complex can also initiate signaling via limited proteolysis of protease-activated receptor-2 (PAR-2). Ahamed et al reported that tissue factor with the disrupted disulfide bond is still competent to engage in signaling, proposing that disulfide-mediated encryption/decryption of tissue factor is a molecular switch between procoagulant and signaling modes.2 They also provided evidence that breaking the Cys186-Cys209 disulfide of tissue factor is under control of nitric oxide pathways, bringing another vascular regulatory process into the mix. View larger version (107K): [in this window] [in a new window]   Figure 1. Tissue factor crystal structure with the sulfur atoms of the proposed labile Cys186-Cys209 disulfide bond in yellow. (Image created from coordinates file 1DAN from the Protein Data Bank.)   In this issue of Blood, Pendurthi and colleagues report negative results from multiple tests of the hypothesis that disulfide formation/disruption controls tissue factor coagulant and signaling activities. These include demonstrating that knocking down PDI expression using siRNA had no effect on cell-surface tissue factor decryption or signaling, nor did adding exogenous PDI or blocking anti-PDI antibodies. Studies supporting the disulfide formation/breakage hypothesis have largely been conducted with living cells, as it is apparently very difficult to demonstrate disulfide-mediated encryption/decryption—or effects of PDI—with purified full-length tissue factor incorporated into phospholipid vesicles.2–4 Those studies have typically demonstrated that treating intact cells with oxidizing agents like HgCl2 causes rapid tissue factor decryption, although such treatments are known to dramatically increase phosphatidylserine exposure.5 Pendurthi and colleagues argue that changes in phospholipid asymmetry, rather than tissue factor disulfide bond rearrangement, most likely explain the procoagulant effects of HgCl2 treatment. Based on multiple lines of reasoning, they call into question the validity of the proposal that tissue factor encryption/decryption involves PDI-dependent disulfide isomerization. It is always difficult to know where the truth lies when 2 groups publish such diametrically opposed con-clusions, and doubtless this new report will spur further research into the puzzling mechanism(s) of tissue factor encryption. Nature does not decrypt her secrets willingly. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Bach RR. Tissue factor encryption. Arterioscler Thromb Vasc Biol 2006; 26:456–461.[Abstract/Free Full Text] Ahamed J, Versteeg HH, Kerver M, et al. Disulfide isomerization switches tissue factor from coagulation to cell signaling. Proc Natl Acad Sci U S A 2006; 103:13932–13937.[Abstract/Free Full Text] Chen VM, Ahamed J, Versteeg HH, et al. Evidence for activation of tissue factor by an allosteric disulfide bond. Biochemistry 2006; 45:12020–12028.[CrossRef][Medline] [Order article via Infotrieve] Versteeg HH and Ruf W. Tissue factor coagulant function is enhanced by protein-disulfide isomerase independent of oxidoreductase activity. J Biol Chem 2007; 282:25416–25424.[Abstract/Free Full Text] Kaneko H, Kakkar VV, Scully MF. Mercury compounds induce a rapid increase in procoagulant activity of monocyte-like U937 cells. Br J Haematol 1994; 87:87–93.[Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Critical importance of the cell system when studying tissue factor de-encryption Hai Po Helena Liang and Philip J. Hogg Blood 2008 112: 912-913. [Full Text] [PDF] Response: Tissue factor de-encryption: the cell model system Usha R. Pendurthi and L. Vijaya Mohan Rao Blood 2008 112: 913. [Full Text] [PDF] Tissue factor activation: is disulfide bond switching a regulatory mechanism? Usha R. Pendurthi, Samit Ghosh, Samir K. Mandal, and L. Vijaya Mohan Rao Blood 2007 110: 3900-3908. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Morrissey, J. H. Search for Related Content PubMed Articles by Morrissey, J. H. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?

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