Keys to the Kingdom: GPCR phosphorylation patterns direct β-arrestin

The β-arrestin proteins are key regulators of G protein-coupled receptors, serving at least three distinct functions: inhibiting receptor signaling through G proteins, directing receptor trafficking from the cell surface after activation, and transmitting receptor-initiated signals directly. How the two β-arrestin proteins perform these many functions for hundreds of receptor types throughout the body, and specifically how β-arrestin-mediated signaling can be tuned to cellular conditions, remains an open question. Function-based evidence and recent structure-based evidence have suggested that patterns of receptor phosphorylation ("barcodes") may be a critical determinant of β-arrestin action. In this issue of EMBO Reports, Baidya and colleagues (Baidya et al, 2020a) report that specific receptor phosphorylation site clusters ("codes") determine whether β-arrestin 1 acts to promote or inhibit receptor activation of Erk mitogen-activated protein kinases. They provide direct evidence for a functional barcode system by transferring inhibitory and stimulatory codes between receptors, suggesting future work to understand just how code site location in a receptor and its phosphorylation status can lead to very different functions of bound β-arrestin proteins.