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.
Kim
Il-Man
IM
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Tilley
Douglas G
DG
Chen
Juhsien
J
Salazar
Natasha C
NC
Whalen
Erin J
EJ
Violin
Jonathan D
JD
Rockman
Howard A
HA
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000526:Alprenolol / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004798:Enzymes / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D018773:Genes, erbB-1 / Q000235:genetics; D006321:Heart / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D000071557:beta-Arrestins
D000319:Adrenergic beta-Antagonists; D019390:Arrestins; D002227:Carbazoles; D004798:Enzymes; D011412:Propanolamines; D011799:Quinazolines; D000071557:beta-Arrestins; D000077261:Carvedilol; D000526:Alprenolol; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
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