Stimulation of the Mitogen-activated Protein Kinase via the A2A-Adenosine Receptor in Primary Human Endothelial Cells
| Autor: | Christoph Höller, Wolfgang Schütz, Michael Freissmuth, Veronika Sexl, Eva Gloria-Maercker, Gudrun Mancusi |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Adenosine
Vasodilator Agents MAPK7 8-Bromo Cyclic Adenosine Monophosphate Adenosine-5'-(N-ethylcarboxamide) Mitogen-activated protein kinase kinase Biology Biochemistry Tropomyosin receptor kinase C MAP2K7 GTP-Binding Proteins Humans ASK1 Enzyme Inhibitors Phosphorylation Molecular Biology MAPK14 Flavonoids Epidermal Growth Factor MAP kinase kinase kinase Isoproterenol Receptors Purinergic P1 Antibodies Monoclonal Cell Biology Molecular biology Enzyme Activation ErbB Receptors Calcium-Calmodulin-Dependent Protein Kinases Tyrosine Fibroblast Growth Factor 2 Cyclin-dependent kinase 9 Endothelium Vascular Thymidine |
| Zdroj: | Journal of Biological Chemistry. 272:5792-5799 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.272.9.5792 |
| Popis: | Adenosine exerts a mitogenic effect on human endothelial cells via stimulation of the A2A-adenosine receptor. This effect can also be elicited by the beta2-adrenergic receptor but is not mimicked by elevation of intracellular cAMP levels. In the present work, we report that stimulation of the A2A-adenosine receptor and of the beta2-adrenergic receptor activates mitogen-activated protein kinase (MAP kinase) in human endothelial cells based on the following criteria: adenosine analogues and beta-adrenergic agonists cause an (i) increase in tyrosine phosphorylation of the p42 isoform and to a lesser extent of the p44 isoform of MAP kinase and (ii) stimulate the phosphorylation of myelin basic protein by MAP kinase; (iii) this is accompanied by a redistribution of the enzyme to the perinuclear region. Pretreatment of the cells with cholera toxin (to down-regulate Gsalpha) abolishes activation of MAP kinase by isoproterenol but not that induced by adenosine analogues. In addition, MAP kinase stimulation via the A2A-adenosine receptor is neither impaired following pretreatment of the cells with pertussis toxin (to block Gi-dependent pathways) nor affected by GF109203X (1 microM; to inhibit typical protein kinase C isoforms) nor by a monoclonal antibody, which blocks epidermal growth factor-dependent signaling. In contrast, MAP kinase activation is blocked by PD 098059, an inhibitor of MAP kinase kinase 1 (MEK1) activation, which also blunts the A2A-adenosine receptor-mediated increase in [3H]thymidine incorporation. Activation of the A2A-adenosine receptor is associated with increased levels of GTP-bound p21(ras). Thus, our experiments define stimulation of MAP kinase as the candidate cellular target mediating the mitogenic action of the A2A-adenosine receptor on primary human endothelial cells; the signaling pathway operates via p21(ras) and MEK1 but is independent of Gi, Gs, and the typical protein kinase C isoforms. This implies an additional G protein which links this prototypical Gs-coupled receptor to the MAP kinase cascade. |
| Databáze: | OpenAIRE |
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