Introduction
The urokinase-urokinase receptor (u-PA-u-PAR) system seems to play a crucial role
in a number of biological processes, including local fibrinolysis, tumor invasion,
angiogenesis, neointima and atherosclerotic plaque formation, inflammation, and matrix
remodeling during wound healing and development.1-6 Binding of urokinase to its specific receptor provides cells with a localized proteolytic
potential. It stimulates conversion of cell surface-bound plasminogen into active
plasmin, which, in turn, is required for proteolytic degradation of basement membrane
components, including fibronectin, collagen, laminin, and proteoglycan core proteins.7 Moreover, plasmin activates other matrix-degrading enzymes, such as matrix metalloproteinases.8 Overexpression of u-PA/u-PAR correlates with tumor invasion and metastasis formation,9-13 while reduction of cell-surface bound u-PA and inhibition of u-PAR expression leads
to a significant decrease of invasive and metastatic activity.14 Specific antagonists that suppress binding of u-PA to u-PAR have been shown to inhibit
cell-surface plasminogen activation, tumor growth, and angiogenesis both in vitro
and in vivo models.15,16
Independently of its proteolytic activity, u-PA is implicated in many biological processes
that seem to require u-PAR-mediated intracellular signal transduction, such as proliferation,
chemotactic movement and adhesion, migration, and differentiation.17 Data obtained in the late 1980s indicated that u-PA not only provides cells with
local proteolytic activity, but might also be capable of transducing signals to the
cell.18-22 At that time, however, the u-PAR has just been isolated, cloned, and identified as
a glycosylphosphatidylinositol (GPI)-linked protein and not a transmembrane protein.
Signaling via the u-PAR was, therefore, regarded as being unlikely, and the effects
of u-PA on cell proliferation18-22 were thought to be mediated by proteolytic activation of latent growth factors. The
assumption of direct signaling via u-PAR was, in fact, considered controversial, until
about 10 years later when a physical association between u-PAR and signaling proteins
was found.23 From this report on, several proteins associated with u-PAR have been identified.
Now, u-PAR seems to be part of a large “signalosome” associated and interacting with
several proteins on both the outside and inside of the cell.
