The plasminogen activating system (PAS) is an ensemble of proteins involved in the extracellular conversion of the ubiquitous inactive plasminogen to the broad spectrum serine protease plasmin, which is implicated in fibrin homeostasis and in numerous physiological and pathological processes requiring the remodelling of extracellular matrix (ECM) and basement membranes (BM). The PAS consists of two serine proteases, the urokinase (uPA) and the tissue-type (tPA) plasminogen activators, the cell membrane receptor for uPA (uPAR) and two main inhibitors belonging to the serine proteinase inhibitors (serpin) superfamily, the plasminogen activator inhibitor 1 (PAI-1), and 2 (PAI-2). The uPA is first synthesized as a single-chain zymogen (pro-uPA or sc-uPA); once secreted in extracellular environs, the sc-uPA is converted to the active disulfide-linked two-chain form (tc-uPA) by a number of proteases such as plasmin, plasma kallikrein, and cathepsin B and L (Choong and Nadesapillai 2003). Plasmin is the primary activator of sc-uPA and is in turn activated by tc-uPA, thus enhancing its own production. Such phenomenon, referred as “reciprocal zymogen activation”, occurs much more efficiently when the sc-uPA is associated with its receptor uPAR, a glycoprotein anchored to the plasma membrane through a glycosyl-phosphatidylinositol moiety (Plesner et al. 1997; Blasi and Carmeliet 2002). As a consequence, the active uPA generation is concentrated in the pericellular area, where it represents an effective and rapid source of plasmin during cell migration and invasion under physiological or pathological conditions. Moreover, in numerous cell types the expression of plasma membrane plasminogen receptors, which colocalize with uPAR, improves the local concentrations of reactants (Castellino and Ploplis 2005).