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

Valentina De Lorenzi, Gian Maria Sarra-Ferraris, Jeppe B Madsen, Michela Lupia, Peter A. Andreasen, Nicolai Sidenius

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)982-98
Number of pages17
JournalEMBO Reports
Volume17
Issue number7
DOIs
Publication statusPublished - Jul 2016

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Vitronectin
Plasminogen
Cell adhesion
Urokinase-Type Plasminogen Activator
Cell Adhesion
Chemical activation
Proteolysis
Fibrinolysin
Plasminogen Activator Inhibitor 1
Tissue homeostasis
Physiological Phenomena
Cell signaling
Feedback
Biological Phenomena
Cell Surface Receptors
Homeostasis

Keywords

  • Journal Article

Cite this

De Lorenzi, V., Sarra-Ferraris, G. M., Madsen, J. B., Lupia, M., Andreasen, P. A., & Sidenius, N. (2016). Urokinase links plasminogen activation and cell adhesion by cleavage of the RGD motif in vitronectin. EMBO Reports, 17(7), 982-98. https://doi.org/10.15252/embr.201541681

Urokinase links plasminogen activation and cell adhesion by cleavage of the RGD motif in vitronectin. / De Lorenzi, Valentina; Sarra-Ferraris, Gian Maria; Madsen, Jeppe B; Lupia, Michela; Andreasen, Peter A.; Sidenius, Nicolai.

In: EMBO Reports, Vol. 17, No. 7, 07.2016, p. 982-98.

Research output: Contribution to journalArticle

De Lorenzi, V, Sarra-Ferraris, GM, Madsen, JB, Lupia, M, Andreasen, PA & Sidenius, N 2016, 'Urokinase links plasminogen activation and cell adhesion by cleavage of the RGD motif in vitronectin', EMBO Reports, vol. 17, no. 7, pp. 982-98. https://doi.org/10.15252/embr.201541681
De Lorenzi, Valentina ; Sarra-Ferraris, Gian Maria ; Madsen, Jeppe B ; Lupia, Michela ; Andreasen, Peter A. ; Sidenius, Nicolai. / Urokinase links plasminogen activation and cell adhesion by cleavage of the RGD motif in vitronectin. In: EMBO Reports. 2016 ; Vol. 17, No. 7. pp. 982-98.
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