uPAR regulates pericellular proteolysis through a mechanism involving integrins and fMLF-receptors
| Autor: | Vincenzo Cosimato, Nunzia Montuori, Loredana Rinaldi, Vincenza Elena Anna Rea, Daniela Alfano, Pia Ragno |
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| Přispěvatelé: | Montuori, Nunzia, V., Cosimato, L., Rinaldi, Rea, VINCENZA ELENA ANNA, D., Alfano, P., Ragno |
| Rok vydání: | 2013 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Pericellular proteolysi Cholera Toxin Integrins urokinase receptor G-PROTEIN Integrin Plasminogen activator GTP-Binding Protein alpha Subunits Gi-Go 030204 cardiovascular system & hematology Ligands Transfection p38 Mitogen-Activated Protein Kinases Receptors Urokinase Plasminogen Activator 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Humans Extracellular Signal-Regulated MAP Kinases skin and connective tissue diseases Receptor Protein Kinase Inhibitors neoplasms biology Kinase Chemistry HEK 293 cells Hematology Receptors Formyl Peptide Urokinase-Type Plasminogen Activator Molecular biology biological factors Up-Regulation Cell biology Urokinase receptor enzymes and coenzymes (carbohydrates) HEK293 Cells 030104 developmental biology Pertussis Toxin biology.protein RNA Interference biological phenomena cell phenomena and immunity HeLa Cells Signal Transduction |
| Zdroj: | Thrombosis and Haemostasis. 109:309-318 |
| ISSN: | 2567-689X 0340-6245 |
| DOI: | 10.1160/th12-08-0546 |
| Popis: | SummaryThe 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. |
| Databáze: | OpenAIRE |
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