Research ArticleGPCR SIGNALING

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

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Sci. Signal.  20 Jun 2017:
Vol. 10, Issue 484, eaal3395
DOI: 10.1126/scisignal.aal3395

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β-Arrestins not necessary

The β2-adrenergic receptor is thought to activate signaling mediated by the kinase ERK through a pathway that does not require G proteins but rather the β-arrestin family of scaffolding proteins. Biased agonists for the β2-adrenergic receptor are being developed to selectively activate this pathway. O’Hayre et al. took advantage of improved technologies for knocking out proteins in cells and unexpectedly found that β-arrestins were not required for ERK activation downstream of the β2-adrenergic receptor, although β-arrestin 2 was required for receptor internalization. Instead, the pathway depended on Gαs, Gβγ, and various other signaling molecules. These results suggest that biased agonists for the β2-adrenergic receptor may exert their effects in a β-arrestin–independent manner.

Abstract

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 small interfering RNAs (siRNAs) to determine the roles of β-arrestin 1 (β-arr1) and β-arr2 in β2AR internalization, trafficking, and signaling to ERK. We found that only β-arr2 was essential for β2AR internalization. Unexpectedly, 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 under pathological conditions.

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