Genetic evidence that β-arrestins are dispensable for the initiation of β-adrenergic receptor signaling to ERK.

The β-adrenergic receptor (βAR) has provided a paradigm to elucidate how G protein-coupled receptors (GPCRs) control intracellular signaling, including the discovery that β-arrestins, which bind to ligand-activated GPCRs, are central for GPCR function. We used genome editing, conditional gene deletion, and small interfering RNAs (siRNAs) to determine the roles of β-arrestin 1 (β-arr1) and β-arr2 in βAR internalization, trafficking, and signaling to ERK. We found that only β-arr2 was essential for βAR internalization. Unexpectedly, β-arr1 and β-arr2 and receptor internalization were dispensable for ERK activation. Instead, βAR signaled through Gα and Gβγ subunits through a pathway that involved the tyrosine kinase SRC, the adaptor protein SHC, the guanine nucleotide exchange factor SOS, the small GTPase RAS, and the kinases RAF and MEK, which led to ERK activation. These findings provide a molecular framework for βAR signaling through β-arrestin-independent pathways in key physiological functions and under pathological conditions.