Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation.

Recent evidence suggests that binding of agonist to its cognate receptor initiates not only classical G protein-mediated signaling, but also beta-arrestin-dependent signaling. One such beta-arrestin-mediated pathway uses the beta(1)-adrenergic receptor (beta(1)AR) to transactivate the EGFR. To determine whether beta-adrenergic ligands that do not activate G protein signaling (i.e., beta-blockers) can ...
stabilize the beta(1)AR in a signaling conformation, we screened 20 beta-blockers for their ability to stimulate beta-arrestin-mediated EGFR transactivation. Here we show that only alprenolol (Alp) and carvedilol (Car) induce beta(1)AR-mediated transactivation of the EGFR and downstream ERK activation. By using mutants of the beta(1)AR lacking G protein-coupled receptor kinase phosphorylation sites and siRNA directed against beta-arrestin, we show that Alp- and Car-stimulated EGFR transactivation requires beta(1)AR phosphorylation at consensus G protein-coupled receptor kinase sites and beta-arrestin recruitment to the ligand-occupied receptor. Moreover, pharmacological inhibition of Src and EGFR blocked Alp- and Car-stimulated EGFR transactivation. Our findings demonstrate that Alp and Car are ligands that not only act as classical receptor antagonists, but can also stimulate signaling pathways in a G protein-independent, beta-arrestin-dependent fashion.
Mesh Terms:
Adrenergic beta-Antagonists, Alprenolol, Animals, Arrestins, Carbazoles, Cell Line, Transformed, Dose-Response Relationship, Drug, Enzyme Activation, Enzymes, Genes, erbB-1, Heart, Humans, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Phosphorylation, Propanolamines, Quinazolines, Receptor, Epidermal Growth Factor, Signal Transduction, Transcriptional Activation
Proc. Natl. Acad. Sci. U.S.A.
Date: Sep. 23, 2008
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