title: uPAR regulates pericellular proteolysis through a mechanism involving integrins and fMLF-receptors.
abstract: 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.
authors.affiliation: Department of Cellular and Molecular Biology and Pathology, Federico II University, Naples, Italy.
authors.forename: Nunzia
authors.initials: N
authors.lastname: Montuori
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cosimato
authors.forename: Loredana
authors.initials: L
authors.lastname: Rinaldi
authors.forename: Vincenza Elena Anna
authors.initials: VE
authors.lastname: Rea
authors.forename: Daniela
authors.initials: D
authors.lastname: Alfano
authors.forename: Pia
authors.initials: P
authors.lastname: Ragno
mesh_terms: D002772:Cholera Toxin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D037342:Pertussis Toxin / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016023:Integrins; D008024:Ligands; C524898:PLAUR protein, human; D047428:Protein Kinase Inhibitors; D044042:Receptors, Formyl Peptide; D055293:Receptors, Urokinase Plasminogen Activator; D002772:Cholera Toxin; D037342:Pertussis Toxin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; D019206:GTP-Binding Protein alpha Subunits, Gi-Go