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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
From the Departments of Pathology and Laboratory Medicine and
Medicine and Pediatrics, University of Pennsylvania, Philadelphia, PA;
the Division of Hematology, Children's Hospital of Philadelphia,
Philadelphia, PA; and American Diagnostica, Inc, Greenwich, CT.
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.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 1987-1998
© 1998 by The American Society of Hematology.
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