[beta]-Blockers aiprenolol and carvedilol stimulate [beta]-arrestin-mediated EGFR transactivation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 38; p. 14555
• Main Authors: Kim, Il-Man, Tilley, Douglas G, Chen, Juhsien, Salazar, Natasha C, Whalen, Erin J, Violin, Jonathan D, Rockman, Howard A
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 23.09.2008
• Subjects: Glycoproteins; Kinases; Molecules; Mutation; Signal transduction
• ISSN: 0027-8424; 1091-6490

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 ...-adrenergic receptor (...) to transactivate the EGFR. To determine whether β-adrenergic ligands that do not activate G protein signaling (i.e., b-blockers) can stabilize the ... in a signaling conformation, we screened 20 β-blockers for their ability to stimulate b-arrestin-mediated EGFR transactivation. Here we show that only alprenolol (Alp) and carvedilol (Car) induce ...-mediated transactivation of the EGFR and downstream ERK activation. By using mutants of the ... lacking G protein-coupled receptor kinase phosphorylation sites and siRNA directed against β-arrestin, we show that Alp- and Car-stimulated EGFR transactivation requires ... 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. (ProQuest: ... denotes formulae/symbols omitted.)