EGF and angiotensin II modulate lysophosphatidic acid LPA1 receptor function and phosphorylation state |
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Authors: | Christian C. Colí n-Santana,S. Eré ndira Avendañ o-Vá zquezRocí o Alcá ntara-Herná ndez,J. Adolfo Garcí a-Sá inz |
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Affiliation: | Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Apartado Postal 70-248, México D. F. 04510, México |
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Abstract: | BackgroundLysophosphatidic acid (LPA) is a local mediator that exerts its actions through G protein coupled receptors. Knowledge on the regulation of such receptors is scarce to date. Here we show that bidirectional cross-talk exits between LPA1 and EGF receptors.MethodsC9 cells expressing LPA1 receptor fussed to the enhanced green fluorescent protein were used. We studied intracellular calcium concentration, Akt/PKB phosphorylation, LPA1 and EGF receptor phosphorylation.ResultsEGF diminished LPA-mediated intracellular calcium response and induced LPA1 receptor phosphorylation, which was sensitive to protein kinase C inhibitors. Angiotensin II and LPA induced EGF receptor transactivation as evidenced by Akt/PKB phosphorylation through metalloproteinase-catalyzed membrane shedding of heparin-binding EGF and autocrine/paracrine activation of EGF receptors. This process was found to be of major importance in angiotensin II-induced LPA1 receptor phosphorylation. Attempts to define a role for EGF receptor transactivation in homologous LPA1 receptor desensitization and phosphorylation suggested that G protein-coupled receptor kinases are the major players in this process, overshadowing other events.ConclusionsEGF receptors and LPA1 receptors are engaged in an intense liaison, in that EGF receptors are capable of modulating LPA1 receptor function through phosphorylation cascades. EGF transactivation plays a dual role: it mediates some LPA actions, and it modulates LPA1 receptor function in inhibitory fashion.General significanceEGF and LPA receptors coexist in many cell types and play key roles in maintaining the delicate equilibrium that we call health and in the pathogenesis of many diseases. The intense cross-talk described here has important physiological and pathophysiological implications. |
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Keywords: | Lysophospatidic acid receptor Epidermal growth factor receptor Transactivation Desensitization Phosphorylation |
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