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.
This study identifies a novel function for the plasminogen activation cascade in the regulation of cell adhesion. Urokinase and plasmin cleave the RGD motif of vitronectin in a process that is accelerated by the urokinase receptor and counteracted by the plasminogen activator inhibitor‐1.
The proteases urokinase (uPA) and plasmin (Pli) inactivate the adhesive activity of vitronectin through cleavage of its RGD motif.
Through its interaction with the somatomedin‐B domain of vitronectin, the urokinase receptor (uPAR) accelerates the process.
The plasminogen activator inhibitor‐1 (PAI‐1) is a proteolysis‐triggered stabilizer of cell adhesion to vitronectin.
Vitronectin is cleaved in vivo and its fragments can be identified in biological fluids.
EMBO Reports (2016) 17: 982–998
- Received October 30, 2015.
- Revision received March 23, 2016.
- Accepted April 19, 2016.
- © 2016 The Authors
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