title: Urokinase links plasminogen activation and cell adhesion by cleavage of the RGD motif in vitronectin.
abstract: Components of the plasminogen activation system including urokinase (uPA), its inhibitor (PAI-1) and its cell surface receptor (uPAR) have been implicated in a wide variety of biological processes related to tissue homoeostasis. Firstly, the binding of uPA to uPAR favours extracellular proteolysis by enhancing cell surface plasminogen activation. Secondly, it promotes cell adhesion and signalling through binding of the provisional matrix protein vitronectin. We now report that uPA and plasmin induces a potent negative feedback on cell adhesion through specific cleavage of the RGD motif in vitronectin. Cleavage of vitronectin by uPA displays a remarkable receptor dependence and requires concomitant binding of both uPA and vitronectin to uPAR Moreover, we show that PAI-1 counteracts the negative feedback and behaves as a proteolysis-triggered stabilizer of uPAR-mediated cell adhesion to vitronectin. These findings identify a novel and highly specific function for the plasminogen activation system in the regulation of cell adhesion to vitronectin. The cleavage of vitronectin by uPA and plasmin results in the release of N-terminal vitronectin fragments that can be detected in vivo, underscoring the potential physiological relevance of the process.
authors.affiliation: Unit of Cell Matrix Signalling, IFOM The FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: De Lorenzi
authors.affiliation: Unit of Cell Matrix Signalling, IFOM The FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Sarra Ferraris
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Jeppe B
authors.initials: JB
authors.lastname: Madsen
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Lupia
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Andreasen
authors.affiliation: Unit of Cell Matrix Signalling, IFOM The FIRC Institute of Molecular Oncology, Milan, Italy nicolai.sidenius@icloud.com.
authors.forename: Nicolai
authors.identifier: 0000-0002-7825-7629
authors.initials: N
authors.lastname: Sidenius
mesh_terms: D020816:Amino Acid Motifs; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D025461:Feedback, Physiological; D005341:Fibrinolysin / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D010958:Plasminogen / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D019096:Vitronectin / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D019096:Vitronectin; D010958:Plasminogen; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator
keywords: RGD; cell adhesion; extracellular proteolysis; urokinase‐type plasminogen activator system; vitronectin