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Vitronectin Concentrates Proteolytic Activity on the Cell Surface
and Extracellular Matrix by Trapping Soluble Urokinase
Receptor-Urokinase Complexes
Triantafyllos Chavakis,
Sandip M. Kanse,
Barbara Yutzy,
H. Roger Lijnen, and
Klaus T. Preissner
From the Max-Planck-Institut, Kerckhoff-Klinik, Bad Nauheim, Germany;
and the Center for Molecular and Vascular Biology, Katholieke
Universiteit Leuven, Leuven, Belgium.
Urokinase-type-plasminogen activator (uPA) and its receptor are
localized in the vessel wall where they are involved in cellular activation and remodelling processes. Besides the cell surface glycolipid (GPI)-anchored urokinase receptor (uPAR), which binds uPA
with high affinity, recent evidence points to the existence of soluble
uPAR (suPAR), as well. In the present study, the origin, binding
mechanism, and cellular effects of suPAR were examined. Under basal
conditions human vascular smooth muscle cells (HVSMC), human umbilical
vein endothelial cells (HUVEC), and monocytic cells released 0.1 to 2 ng/mL suPAR, which was increased twofold to fivefold after phorbol
ester (PMA) stimulation, as measured by a function-dependent
enzyme-linked immunosorbent assay (ELISA). suPAR alone did not bind to
HVSMC or HUVEC, but reduced cellular uPA binding by 50% to 70%.
However, after removal of GPI-uPAR with phosphatidylinositol-specific
phospholipase C, suPAR dose-dependently increased uPA binding by
fourfold to fivefold. This increase in binding was completely inhibited
by vitronectin (VN) and by a monoclonal antibody against VN, but not by
other matrix proteins or antibodies. Thus, VN-mediated uPA binding to
cells was regulated by the ratio of soluble to surface-associated
uPAR. In a uPAR-deficient cell line (LM-TK ), suPAR
increased uPA binding up to 10-fold, whereas the truncated receptor
lacking the amino-terminal uPA-binding domain was ineffective. The
formation of a ternary uPA/suPAR/VN-complex on the cell surface and the
free extracellular matrix could be inhibited by a monoclonal antibody
against VN, as well as by plasminogen activator inhibitor-1 (PAI-1).
Moreover, VN-mediated binding of the uPA/suPAR-complex led to a
fivefold increase in plasminogen activator activity. Through this novel
pathway, VN concentrates the uPA/suPAR-complex to cell surfaces and
extracellular matrix sites, leading to the accumulation of plasminogen
activator activity required for cell migration and tissue remodelling
processes.
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2305-2312
© 1998 by The American Society of Hematology.
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