Genetic evidence that β-arrestins are dispensable for the initiation of β2-adrenergic receptor signaling to ERK

Abstract

<p class="first" id="P1">The β2 adrenergic receptor (β2AR) 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 siRNAs to determine the roles of β-arrestin (β-arr) 1 and 2 in β2AR internalization, trafficking, and signaling to ERK. We found that only β-arr2 was essential for β2AR internalization. Surprisingly, β-arr1 and β-arr2 and receptor internalization were dispensable for ERK activation. Instead, β2AR signaled through Gαs 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 β2AR signaling through β-arrestin-independent pathways in key physiological functions and pathological conditions. </p>