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Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 2075-2083
Lysis of Plasma Clots by Urokinase-Soluble Urokinase Receptor
Complexes
Abd Al-Roof Higazi,
Khalil Bdeir,
Edna Hiss,
Shira Arad,
Alice Kuo,
Iyad Barghouti, and
Douglas B. Cines
From the Department of Clinical Biochemistry, Hadassah University
Hospital and Hebrew University-Hadassah Medical School, Jerusalem,
Israel; and the Department of Pathology and Laboratory Medicine,
Hospital of the University of Pennsylvania, Philadelphia, PA.
Single-chain urokinase plasminogen activator (scuPA), the unique
form secreted by cells, expresses little intrinsic plasminogen activator activity. scuPA can be activated by proteolytic cleavage to
form a two-chain enzyme (tcuPA), which is susceptible to inhibition by
plasminogen activator inhibitor type I (PAI-1). scuPA is also activated
when it binds to its cellular receptor (uPAR), in which case the
protein remains as a single chain molecule with less susceptibility to
PAIs. Fibrin clots are invested with PAI-1 derived from plasma and from
activated platelets. Therefore, we compared the fibrinolytic activity
of complexes between scuPA and recombinant soluble uPAR (suPAR) to that
of scuPA, tcuPA, and tcuPA/suPAR complexes. scuPA/suPAR complexes
mediated the lysis of plasma-derived fibrin clots 14-fold more
extensively than did equimolar concentrations of scuPA and threefold
more extensively than did tcuPA or tcuPA/suPAR, respectively. The
enhanced catalytic activity of scuPA/suPAR required that all three
domains of the receptor be present, correlated with its PAI-1
resistance, was not dependent on fibrin alone, and required a plasma
cofactor that was identified as IgG. Human IgG bound specifically to
suPAR and scuPA/suPAR as determined by using affinity chromatography
and immunoprecipitation. Plasma depleted of IgG lost most of its
capacity to promote the fibrinolytic activity of scuPA/suPAR, and the
activity of the complex was restored by adding plasma concentrations of
purified IgG. These studies indicate that scuPA/suPAR can function as a
plasminogen activator in a physiological milieu.
© 1998 by The American Society of Hematology.
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