uPAR regulates pericellular proteolysis through a mechanism involving integrins and fMLF-receptors

Nunzia Montuori; Vincenzo Cosimato; Loredana Rinaldi; Vincenza Elena Anna Rea; Daniela Alfano; Pia Ragno

doi:10.1160/TH12-08-0546

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2013; 109(02): 309-318
DOI: 10.1160/TH12-08-0546

Cellular Proteolysis and Oncology

Schattauer GmbH

uPAR regulates pericellular proteolysis through a mechanism involving integrins and fMLF-receptors

Nunzia Montuori^*

¹Department of Cellular and Molecular Biology and Pathology, “Federico II” University, Naples, Italy

,

Vincenzo Cosimato^*

²Department of Chemistry and Biology, University of Salerno, Fisciano (Salerno), Italy

,

Loredana Rinaldi

²Department of Chemistry and Biology, University of Salerno, Fisciano (Salerno), Italy

,

Vincenza Elena Anna Rea

¹Department of Cellular and Molecular Biology and Pathology, “Federico II” University, Naples, Italy

,

Daniela Alfano^§

²Department of Chemistry and Biology, University of Salerno, Fisciano (Salerno), Italy

,

Pia Ragno

²Department of Chemistry and Biology, University of Salerno, Fisciano (Salerno), Italy

› Institutsangaben

Abstract

Summary

The expression of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR) can be regulated by several hormones, cytokines, and tumour promoters. uPAR is a glycosyl-phosphatidyl inositol (GPI)- linked cell-surface protein; however, it is capable to transduce signals inside the cell by interacting with other cell-surface proteins, such as integrins and G-protein coupled (GPC) receptors. We previously reported that uPAR cell-surface expression can be positively regulated by its ligand, uPA, independently of its proteolytic activity. We now demonstrate that uPAR overexpression induces or increases uPA secretion both in uPAR-negative and in uPAR-expressing cells. Accordingly, uPAR depletion impairs uPA expression in cells which constitutively express both uPA and its receptor. uPAR exerts its regulatory effect through the activation of the ERK mitogen-activated protein kinases (MAPKs), whereas the p-38 MAPK is not involved. Overexpression of truncated forms of uPAR, lacking the N-terminal domain (DI) and not able to interact with membrane co-receptors, failed to increase uPA expression. Inhibition of uPAR-integrin interaction by the specific P-25 peptide, as well as Gi-protein inhibition by cholera pertussin toxin or depletion of the GPC receptors for fMLF (fMLF-Rs) also impaired uPAR capability to regulate uPA expression. These findings demonstrate that uPAR, whose expression is regulated by uPA, can, in turn, regulate uPA expression through a mechanism involving its functional interaction with integrins and fMLF-Rs.

Keywords

Urokinase receptor - plasminogen activators - pericellular proteolysis

Volltext

Referenzen

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