New Roles for β-Arrestins in Cell Signaling: Not Just for Seven-Transmembrane Receptors  Robert J. Lefkowitz, Keshava Rajagopal, Erin J. Whalen  Molecular Cell  Volume 24, Issue 5, Pages 643-652 (December 2006) DOI: 10.1016/j.molcel.2006.11.007 Copyright © 2006 Elsevier Inc. Terms and Conditions

Figure 1 Model of Inactive and Active Conformations of β-Arrestin2 The inactive conformation of β-arrestin2 displaying an intact polar core at the junction of N and C domains with the C tail in close proximity to the junction. Activation of β-arrestin2 via interaction with the phosphorylated tail of an activated receptor promotes the disruption of the polar core and allows for release of the C tail, exposing both clathrin and AP2-binding domains. (Model is adapted from Xiao et al. [2004].) Molecular Cell 2006 24, 643-652DOI: (10.1016/j.molcel.2006.11.007) Copyright © 2006 Elsevier Inc. Terms and Conditions

Figure 2 β-Arrestins at the Crossroads of Ubiquitination and Receptor Signaling (1) MDM2 binds and ubiquitinates receptor-associated β-arrestin, promoting clathrin and AP2 recruitment, receptor internalization, and β-arrestin-mediated signaling. (2) β-arrestins facilitate receptor ubiquitination, serving as adaptors to bring E3 ligases into proximity with the receptors, thereby promoting receptor trafficking to lysosomes for degradation. (3) β-arrestin1 serves as an adaptor to bring the E3 ligase MDM2 to the activated IGF-1 receptor, thereby promoting receptor ubiquitination and subsequent proteasomal degradation. (4) β-arrestins compete with IRS-1 for MDM2, thereby decreasing insulin-induced MDM2-mediated ubiquitination and proteasomal degradation of IRS-1. β-arrestins thus enhance insulin sensitivity. (5) Insulin stimulation promotes β-arrestin phosphorylation, ubiquitination, and downregulation, thereby increasing 7TMR-mediated G protein signaling and decreasing β-arrestin-mediated signaling, e.g., to ERK. (6) In Drosophila melanogaster, the nonvisual arrestin homolog Kurtz interacts with the ubiquitin ligase Deltex to facilitate Notch ubiquitination. Notch ubiquitination promotes its proteasomal degradation. Molecular Cell 2006 24, 643-652DOI: (10.1016/j.molcel.2006.11.007) Copyright © 2006 Elsevier Inc. Terms and Conditions

Figure 3 Conventional versus Biased Seven-Transmembrane Receptor Signaling (A) Agonist-stimulated 7TMR signaling via both heterotrimeric G proteins and β-arrestins. (B) Conventional antagonists bind 7TMRs and prevent agonist stimulated signaling through both heterotrimeric G proteins and β-arrestins. (C) Biased antagonists/agonists (e.g., SII-angiotensin II) block agonist stimulated heterotrimeric G protein signaling while promoting β-arrestin signaling. Molecular Cell 2006 24, 643-652DOI: (10.1016/j.molcel.2006.11.007) Copyright © 2006 Elsevier Inc. Terms and Conditions