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Tissue Factor Regulates Plasminogen Binding and Activation
Journal article   Open access   Peer reviewed

Tissue Factor Regulates Plasminogen Binding and Activation

Zhiqiang Fan, Peter J. Larson, John Bognacki, P.N. Raghunath, John E. Tomaszewski, Alice Kuo, Gabriela Canziani, Irwin Chaiken, Douglas B. Cines and Abd Al-Roof Higazi
Blood, v 91(6), pp 1987-1998
15 Mar 1998
DOI: https://doi.org/10.1182/blood.V91.6.1987.1987_1987_1998
PMID: 9490681
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://ashpublications.org/blood/article-pdf/91/6/1987/239992/1987.pdfView
Published, Version of Record (VoR) Open
url
https://doi.org/10.1182/blood.V91.6.1987.1987_1987_1998View
Published, Version of Record (VoR) Open

Abstract

Tissue factor (TF) has been implicated in several important biologic processes, including fibrin formation, atherogenesis, angiogenesis, and tumor cell migration. In that plasminogen activators have been implicated in the same processes, the potential for interactions between TF and the plasminogen activator system was examined. Plasminogen was found to bind directly to the extracellular domain of TF apoprotein (amino acids 1-219) as determined by optical biosensor interaction analysis. A fragment of plasminogen containing kringles 1 through 3 also bound to TF apoprotein, whereas isolated kringle 4 and miniplasminogen did not. Expression of TF on the surface of a stably transfected Chinese hamster ovary (CHO) cell line stimulated plasminogen binding to the cells by 70% more than to control cells. Plasminogen bound to a site on the TF apoprotein that appears to be distinct from the binding site for factors VII and VIIa as judged by a combination of biosensor and cell assays. TF enhanced two-chain urokinase (tcuPA) activation of Glu-plasminogen, but not of miniplasminogen, in a dose-dependent, saturable manner (half maximal stimulation at 59 pmol/L). TF apoprotein induced an effect similar to that of relipidated TF, but a relatively higher concentration of the apoprotein was required (half maximal stimulation at 3.8 nmol/L). The stimulatory effect of TF on plasminogen activation was confirmed when plasmin formation was examined directly on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In accord with this, TF inhibited fibrinolysis by approximately 74% at a concentration of 14 nmol/L and almost totally inhibited the binding of equimolar concentrations of plasminogen to human umbilical vein endothelial cells and human trophoblasts. Further, CHO cells expressing TF inhibited uPA-mediated fibrinolysis relative to a wild-type control. TF apoprotein and plasminogen were found to colocalize in atherosclerotic plaque. These data suggest that plasminogen localization and activation may be modulated at extravascular sites through a high-affinity interaction between kringles 1 through 3 of plasminogen and the extracellular domain of TF.

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Hematology
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