First name
Valentina
Last name
De Lorenzi
Year of Study
Thesis Title
Cross-talk between the proteolytic and non-proteolytic functions of the urokinase receptor
Thesis Abstract
Urokinase (uPA) and its cellular receptor (uPAR) have been implicated in many pathological events, such as tumour cell migration and dissemination. The binding of uPA to uPAR favours extracellular proteolysis by enhancing plasminogen activation. Moreover, it promotes cell adhesion and signalling through binding to the provisional matrix protein vitronectin (VN). We here report that plasminogen activation induces a negative feedback on cell adhesion to VN, mainly through the proteolytic cleavage of the RGD-motif in VN. The cell-adhesive properties of VN are impaired by disruption of the integrin binding site and release of the somatomedin B (SMB) domain responsible for uPAR binding. VN represents the first described uPAR-dependent substrate of uPA. Our findings therefore identify a potential novel function of uPAR in focusing the activity of the plasminogen activation system onto extracellular matrix-associated VN. SMB-containing VN fragments are released by several cancer cell lines and detectable in
human urines. Our hypothesis is that they might represent a novel cancer biomarker as a functional measurement of the uPA-system activity in the tumour tissue and we have developed a clinical grade immunoassay for the quantification of such fragments in urine samples. Finally, we show that the urokinase inhibitor, PAI-1, blocks the feedback mediated by uPA and behaves as a uPA-dependent agonist of the uPAR-VN interaction. We report that the uPA·PAI-1 complex displays higher agonistic activity than uPA. These data might represent a molecular explanation for the poor clinical outcome observed in cancer patients with high levels of uPA and PAI-1.
human urines. Our hypothesis is that they might represent a novel cancer biomarker as a functional measurement of the uPA-system activity in the tumour tissue and we have developed a clinical grade immunoassay for the quantification of such fragments in urine samples. Finally, we show that the urokinase inhibitor, PAI-1, blocks the feedback mediated by uPA and behaves as a uPA-dependent agonist of the uPAR-VN interaction. We report that the uPA·PAI-1 complex displays higher agonistic activity than uPA. These data might represent a molecular explanation for the poor clinical outcome observed in cancer patients with high levels of uPA and PAI-1.
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