beta-Arrestin mediates beta1-adrenergic receptor-epidermal growth factor receptor interaction and downstream signaling.
beta1-Adrenergic receptor (beta1AR) stimulation confers cardioprotection via beta-arrestin-de pend ent transactivation of epidermal growth factor receptors (EGFRs), however, the precise mechanism for this salutary process is unknown. We tested the hypothesis that the beta1AR and EGFR form a complex that differentially directs intracellular signaling pathways. beta1AR stimulation and EGF ligand can each induce equivalent EGFR phosphorylation, internalization, and downstream activation of ERK1/2, but only EGF ligand causes translocation of activated ERK to the nucleus, whereas beta1AR-stimulated/EGFR-transactivated ERK is restricted to the cytoplasm. beta1AR and EGFR are shown to interact as a receptor complex both in cell culture and endogenously in human heart, an interaction that is selective and undergoes dynamic regulation by ligand stimulation. Although catecholamine stimulation mediates the retention of beta1AR-EGFR interaction throughout receptor internalization, direct EGF ligand stimulation initiates the internalization of EGFR alone. Continued interaction of beta1AR with EGFR following activation is dependent upon C-terminal tail GRK phosphorylation sites of the beta1AR and recruitment of beta-arrestin. These data reveal a new signaling paradigm in which beta-arrestin is required for the maintenance of a beta1AR-EGFR interaction that can direct cytosolic targeting of ERK in response to catecholamine stimulation.
Tilley
Douglas G
DG
Department of Medicine, Duke University, Medical Center, Durham, North Carolina 27710, USA.
Kim
Il-Man
IM
Patel
Priyesh A
PA
Violin
Jonathan D
JD
Rockman
Howard A
HA
D019390:Arrestins / Q000235:genetics* / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis / Q000378:metabolism; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology; D008024:Ligands; D010766:Phosphorylation; D011485:Protein Binding; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D015398:Signal Transduction; D000071557:beta-Arrestins
D019390:Arrestins; D002395:Catecholamines; D008024:Ligands; D018342:Receptors, Adrenergic, beta-1; D000071557:beta-Arrestins; D066246:ErbB Receptors; D054768:G-Protein-Coupled Receptor Kinases; D048049:Extracellular Signal-Regulated MAP Kinases