Urokinase links plasminogen activation and cell adhesion by cleavage of the RGD motif in vitronectin

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Valentina De Lorenzi, Unit of Cell Matrix Signalling, IFOM The FIRC Institute of Molecular Oncology, Milan, Italy.
  • ,
  • Gian Maria Sarra Ferraris, Unit of Cell Matrix Signalling, IFOM The FIRC Institute of Molecular Oncology, Milan, Italy.
  • ,
  • Jeppe B Madsen, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
  • ,
  • Michela Lupia, Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
  • ,
  • Peter A Andreasen, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
  • ,
  • Nicolai Sidenius, Unit of Cell Matrix Signalling, IFOM The FIRC Institute of Molecular Oncology, Milan, Italy nicolai.sidenius@icloud.com.

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.

Original languageEnglish
JournalE M B O Reports
Volume17
Issue7
Pages (from-to)982-998
Number of pages17
ISSN1469-221X
DOIs
Publication statusPublished - Jul 2016

    Research areas

  • Journal Article

See relations at Aarhus University Citationformats

ID: 103890974