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Interaction of single-chain urokinase with its receptor induces the
appearance and disappearance of binding epitopes within the resultant
complex for other cell surface proteins
AA Higazi, RH Upson, RL Cohen, J Manuppello, J Bognacki, J Henkin, KR McCrae, MZ Kounnas, DK Strickland, KT Preissner, J Lawler and DB Cines
Department of Pathology and Laboratory Medicine, Hospital of the University
of Pennsylvania, Philadelphia 19104, USA.
Binding of urokinase-type plasminogen activator (uPA) to its
glycosylphosphatidylinositol-anchored receptor (uPAR) initiates signal
transduction, adhesion, and migration in certain cell types. To determine
whether some of these activities may be mediated by associations between
the uPA/uPAR complex and other cell surface proteins, we studied the
binding of complexes composed of recombinant, soluble uPA receptor (suPAR)
and single chain uPA (scuPA) to a cell line (LM-TK- fibroblasts) that does
not express glycosylphosphatidylinositol (GPI)-anchored proteins to
eliminate potential competition by endogenous uPA receptors. scuPA induced
the binding of suPAR to LM-TK- cells. Binding of labeled suPAR/scuPA was
inhibited by unlabeled complex, but not by scuPA or suPAR added separately,
indicating cellular binding sites had been formed that are not present in
either component. Binding of the complex was inhibited by low molecular
weight uPA (LMW-uPA) indicating exposure of an epitope found normally in
the isolated B chain of two chain uPA (tcuPA), but hidden in soluble scuPA.
Binding of LMW-uPA was independent of its catalytic site and was associated
with retention of its enzymatic activity. Additional cell binding epitopes
were generated within suPAR itself by the aminoterminal fragment of scuPA,
which itself does not bind to LM-TK- cells. When scuPA bound to suPAR, a
binding site for alpha 2-macroglobulin receptor/LDL receptor-related
protein (alpha 2 MR/LRP) was lost, while binding sites for cell-associated
vitronectin and thrombospondin were induced. In accord with this, the
internalization and degradation of cell-associated tcuPA and tcuPA-PAI- 1
complexes proceeded less efficiently in the presence of suPAR. Further,
little degradation of suPAR was detected, suggesting that cell- bound
complex dissociated during the initial stages of endocytosis. Thus, the
interaction of scuPA with its receptor causes multiple functional changes
within the complex including the dis-appearance of an epitope in scuPA
involved in its clearance from the cell surface and the generation of novel
epitopes that promote its binding to proteins involved in cell adhesion and
signal transduction.
Volume 88,
Issue 2,
pp. 542-551,
07/15/1996
Copyright © 1996 by The American Society of Hematology
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