β-Arrestin Goes Nuclear

Arrestins are a family of scaffolding proteins that are closely associated with the function of seven transmembrane domain G protein-coupled receptors (GPCRs). In mammals, two members of the arrestin family, the visual arrestins, are restricted to photoreceptor cells, whereas two others, β-arrestin 1 and β-arrestin 2, are expressed ubiquitously. These proteins promote the internalization and desensitization of GPCRs (Ferguson et al., 1996; Lohse et al., 1990). Following agonist-induced phosphorylation of GPCRs by kinases, arrestins move from the cytoplasm to the plasma membrane and bind to the phosphorylated receptors. The interaction of arrestins with phosphorylated GPCRs leads to an uncoupling of G protein-dependent receptor signaling (receptor desensitization). Arrestins also promote receptor internalization by recruiting the endocytic machinery. However, recently it has become evident that the biological functions of arrestins go well beyond these wellestablished roles. It is becoming clear that arrestins promote signal transduction by GPCRs. Both β-arrestin 1 and βarrestin 2 act as molecular scaffolds that recruit signaling molecules such as kinases and phosphatases to the activated receptors (Beaulieu et al., 2005; Luttrell et al., 1999; Shenoy and Lefkowitz, 2003). Formation of β-arrestin-based signaling complexes facilitates the activation and/or inhibition of these signaling molecules (Shenoy and Lefkowitz, 2003). The scaffolding/signaling functions of β-arrestins have been studied extensively in heterologous and homologous cellular systems, and in vivo a β-arrestin 2/PP2A/Akt signaling complex is critical for D2 dopamine receptor-dependent behaviors in mice (Beaulieu et al., 2005). During development, βarrestins may have a role in signaling by the seven transmembrane domain receptor proteins frizzled and smoothened (Chen et al., 2004). β-arrestins translocate to these receptors in a phosphorylation-dependent manner. In zebrafish, downregulation of βarrestin 2 results in a disruption of hedgehog/patched/ smoothened function during development (Wilbanks et al., 2004), suggesting that β-arrestins act either as positive regulators or as mediators of signaling in these systems. In this issue of Cell, Kang et al. (2005) have uncovered yet another unexpected function of arrestins. Since their initial characterization, arrestins have been thought of as cytoplasmic proteins that could be recruited to the plasma membrane and endocytic compartments following receptor activation. Although β-arrestin 2 and visual arrestins appear to be found exclusively in β-Arrestin Goes Nuclear