10.1073/pnas.0804745105 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 β-adrenergic receptor (βAR) to transactivate the EGFR. To determine whether β-adrenergic ligands that do not activate G protein signaling (i.e., β-blockers) can stabilize the βAR 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 βAR-mediated transactivation of the EGFR and downstream ERK activation. By using mutants of the βAR lacking G protein-coupled receptor kinase phosphorylation sites and siRNA directed against β-arrestin, we show that Alp- and Car-stimulated EGFR transactivation requires βAR 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.
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