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Blood, 1 December 2007, Vol. 110, No. 12, pp. 3900-3908. Prepublished online as a Blood First Edition Paper on August 28, 2007; DOI 10.1182/blood-2007-07-101469. This Article Full Text (PDF) All Versions of this Article: blood-2007-07-101469v1 110/12/3900    most recent 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 Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pendurthi, U. R. Articles by Rao, L. V. M. Search for Related Content PubMed PubMed Citation Articles by Pendurthi, U. R. Articles by Rao, L. V. M. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 16, 2007 Accepted August 23, 2007 Tissue factor activation: is disulfide bond switching a regulatory mechanism? Usha R. Pendurthi, Samit Ghosh, Samir K. Mandal, and L. Vijaya Mohan Rao* Biomedical Research Division, The University of Texas Health Center at Tyler, Tyler, TX, United States * Corresponding author; email: vijay.rao{at}uthct.edu. A majority of tissue factor (TF) on cell surfaces exists in a cryptic form i.e., coagulantly inactive while retaining its functionality in cell signaling. Recent studies have suggested that cryptic TF contains unpaired cysteine thiols and that activation involves the formation of the disulfide bond Cys186-Cys 209 (Chen et al., Biochemistry 45: 12020-12028, 2006) and that protein disulfide isomerase (PDI) regulates TF coagulant and signaling activities by targeting this disulfide bond (Ahamed et al., PNAS 103: 13932-13937, 2006). This study was carried out to investigate the validity of this novel concept. Although treatment of MDA 231 tumor cells, fibroblasts and stimulated endothelial cells with the oxidizing agent HgCl2 markedly increased the cell surface TF coagulant activity, the increase is associated with increased anionic phospholipids at the cell surface. Annexin V, which binds to anionic phospholipids, attenuated the increased TF coagulant activity. Interestingly, treatment of cells with reducing agents also increased the cell surface TF activity. No evidence was found for either detectable expression of PDI at the cell surface or association of TF with PDI. Exposure of tumor cells to various proteases failed to transport intracellular PDI to the cell surface, and inhibition of PDI by antibodies or reduction of its expression by gene silencing had no effect on either TF coagulant or cell signaling functions. Similarly addition of recombinant PDI had no effect on the cell surface TF activity. Our data suggest that an increase in anionic phospholipids following Hg2+ treatment is responsible for increased TF coagulant activity. These data in conjunction with the negative evidence for any association of free thiols or PDI with TF procoagulant activity undermines the recently proposed hypothesis that PDI-mediated disulfide exchange plays a role in regulating TF procoagulant and cell signaling functions. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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