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β-Blockers alprenolol and carvedilol stimulate β-arrestin-mediated EGFR transactivation
- Kim, Il-Man, Tilley, Douglas G., Chen, Juhsien, Salazar, Natasha C., Whalen, Erin J., Violin, Jonathan D., Rockman, Howard A.
- Proceedings of the National Academy of Sciences of the United States of America 2008 v.105 no.38 pp. 14555-14560
- G-protein coupled receptors, agonists, antagonists, beta-adrenergic antagonists, ligands, mitogen-activated protein kinase, mutants, phosphorylation, signal transduction, small interfering RNA, transcriptional activation
- Recent evidence suggests that binding of agonist to its cognate receptor initiates not only classical G protein-mediated signaling, but also β-arrestin-dependent signaling. One such β-arrestin-mediated pathway uses the β₁-adrenergic receptor (β₁AR) to transactivate the EGFR. To determine whether β-adrenergic ligands that do not activate G protein signaling (i.e., β-blockers) can stabilize the β₁AR in a signaling conformation, we screened 20 β-blockers for their ability to stimulate β-arrestin-mediated EGFR transactivation. Here we show that only alprenolol (Alp) and carvedilol (Car) induce β₁AR-mediated transactivation of the EGFR and downstream ERK activation. By using mutants of the β₁AR lacking G protein-coupled receptor kinase phosphorylation sites and siRNA directed against β-arrestin, we show that Alp- and Car-stimulated EGFR transactivation requires β₁AR phosphorylation at consensus G protein-coupled receptor kinase sites and β-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, β-arrestin-dependent fashion.