IntroductionThe serine proteases urokinase-type plasminogen activator (uPA) and plasmin, in concert with other proteolytic enzymes (e. g. matrix metalloproteases, cysteine proteases), are involved in tumor-associated processes such as cell invasion and regulation of cell/cell and cell/matrix contacts Schmitt et al., 2000;Andreasen et al., 2000). (pro-)uPA binds to a specific, high-affinity cell surface receptor, uPAR (CD87), which is composed of three structurally homologous, independently folded domains (Dear and Medcalf, 1998). In addition, there are also cellular binding sites for plasmin(ogen) (Félez, 1998). In consequence, binding of (pro-) uPA to cell membrane-anchored uPAR significantly increases plasmin generation due to a distinct increase of reciprocal activation of pro-uPA and plasminogen (Ellis et al., 1991). Plasmin not only degrades a variety of components of the extracellular matrix (e. g. fibrin and laminin), but also activates certain matrix metalloproteases (in addition to pro-uPA) which break down additional structural proteins of the extracellular matrix such as various collagens. Thus, cell surface-triggered plasminogen activation plays a fundamental role in tissue remodeling, which is a prerequisite for tumor cell invasion and metastasis Schmitt et al., 2000;Andreasen et al., 2000).The interaction of pro-uPA or its activated form high molecular weight (HMW-)uPA with uPAR has been characterised in detail. Although the N-terminal domain I of uPAR contains major determinants for uPA-binding, high affinity interaction with uPA is dependent on the multidomain structure of the receptor, indicating that all three protein domains are involved in the formation of a composite ligand binding site (Ploug, 1998;Gårdsvoll et al., 1999;Bdeir et al., 2000). In contrast, uPA binds to uPAR via a defined continuous peptide sequence
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