Abstract 5873: Gβγ-dependent Transactivation of the Epidermal Growth Factor Receptor by the Urotensin-II Receptor
Urotensin II (U-II) and its 7 trans-membrane-domain receptor (UTR) are highly expressed in the heart and blood vessels and are up-regulated during heart failure. Several intracellular U-II effects are mediated by the transactivation of the epidermal growth factor receptor (EGFR) and induction of MAPKs. However, the mechanisms underlying this signaling mechanism are still unclear. In this study we tested the hypothesis that released Gβγ subunits after agonist stimulation might play an important role in this process. HEK293 cells overexpressing EGFR and UTR were stimulated with U-II in the presence or absence of its competitive inhibitor Urantide (UR). U-II stimulation induced phosphorylation and internalization of the EGFR, induction of pERK and membrane translocation of β-arrestin 2. These effects were inhibited by pre-treatment with UR. To block the action of Gâã, HEK293 cells were infected with adenovirus encoding the carboxyl terminus of the beta-adrenergic receptor kinase (âARKct), and stimulated with U-II. In âARKct-infected cells, a significant reduction of EGFR transactivation and ERK phosphorylation was observed. Interestingly, U-II treatment significantly reduced apoptotic cell death induced by serum withdrawal, as shown by annexin-propidium iodide staining and TUNEL assay (Table⇓). Importantly, in âARKct-infected cells the anti-apoptotic effect of U-II was significantly reduced as shown by propidium iodide staining and caspase 3 activity (Table⇓). In conclusion, we show a new mechanism of signaling for the UTR which is mediated by EGFR transactivation and promoting cell survival through Gβγ subunits. These findings may provide a mechanism for the role of U-II in cardiovascular responses to injury.