β-Arrestin Mediates β1-Adrenergic Receptor-Epidermal Growth Factor Receptor Interaction and Downstream Signaling

beta 1-Adrenergic receptor (beta 1AR) stimulation confers cardioprotection via beta-arrestin-dependent transactivation of epidermal growth factor receptors (EGFRs), however, the precise mechanism for this salutary process is unknown. We tested the hypothesis that the beta 1AR and EGFR form a complex that differentially directs intracellular signaling pathways. beta 1AR 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 beta 1AR-stimulated/EGFR-transactivated ERK is restricted to the cytoplasm. beta 1AR 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 beta 1AR-EGFR interaction throughout receptor internalization, direct EGF ligand stimulation initiates the internalization of EGFR alone. Continued interaction of beta 1AR with EGFR following activation is dependent upon C-terminal tail GRK phosphorylation sites of the beta 1AR and recruitment of beta-arrestin. These data reveal a new signaling paradigm in which beta-arrestin is required for the maintenance of a beta 1AR-EGFR interaction that can direct cytosolic targeting of ERK in response to catecholamine stimulation.