β-arrestin-mediated receptor trafficking and signal transduction

Abstract

β-arrestins function as endocytic adaptors and mediate trafficking of a variety of cell-surface receptors, including seven-transmembrane receptors (7TMRs). In the case of 7TMRs, β-arrestins carry out these tasks while simultaneously inhibiting upstream G protein-dependent signaling and promoting alternate downstream signaling pathways. The mechanisms by which β-arrestins interact with a continuously expanding ensemble of protein partners and perform their multiple functions including trafficking and signaling are currently being uncovered. Molecular changes at the level of protein conformation as well as posttranslational modifications of β-arrestins likely form the basis for their dynamic interactions during receptor trafficking and signaling. It is becoming increasingly evident that β-arrestins, originally discovered as 7TMR adaptor proteins, indeed have much broader and more versatile roles in maintaining cellular homeostasis. Here we review the traditional and novel functions of β-arrestins and discuss the molecular attributes that might facilitate it multiple interactions in regulating cell signaling and receptor trafficking.

The roles of macrophage autophagy in atherosclerosis

“…For example, β-arrestins, which are traditionally recognized as modulators of the desensitization and inactivation of G protein-coupled receptors (GPCRs), have recently been reported to take part in many signaling pathways, independent of G proteins, as scaffold proteins, and this is increasingly being studied [64] . A previous study in our lab indicated that β-arrestin-1, but not β-arrestin-2, induced Beclin1-dependent autophagy in neurons, which revealed a neuroprotective role for β-arrestin-1 in cerebral ischemia.…”

Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

“…One of the many examples that the ubiquitously expressed arrestins serve as more than terminators of receptor signaling through initiating receptor internalization (Groer et al, 2011;Shenoy and Lefkowitz, 2011;Shukla et al, 2011) is the phenotype of mice lacking b-arrestin 2 (b-arr2À/À; Bohn et al, 1999Bohn et al, , 2002Raehal and Bohn, 2011). As morphine does not induce significant internalization of the mu opioid receptor, the effects of morphine in b-arr2À/À mice cannot be explained by this prototypical role of barrestin 2.…”

Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

“…Although its main function is the modulation of receptor number on the cell surface, thereby adjusting the sensitivity of the cell to external stimuli, it also plays role in the resensitization and signaling of GPCRs (Ferguson, 2001;Hunyady and Catt, 2006;Shenoy and Lefkowitz, 2011). At the molecular level, β-arrestins are key regulatory proteins of receptor internalization, as they can bind to activated GPCRs, as well as to clathrin and the adaptor protein AP-2, thus directing the receptor towards clathrin-mediated endocytosis (Shenoy and Lefkowitz, 2011). β-arrestins also mediate receptor desensitization, as their binding to the activated GPCRs causes the uncoupling of the receptor from its cognate G protein (Shenoy and Lefkowitz, 2011).…”

“…At the molecular level, β-arrestins are key regulatory proteins of receptor internalization, as they can bind to activated GPCRs, as well as to clathrin and the adaptor protein AP-2, thus directing the receptor towards clathrin-mediated endocytosis (Shenoy and Lefkowitz, 2011). β-arrestins also mediate receptor desensitization, as their binding to the activated GPCRs causes the uncoupling of the receptor from its cognate G protein (Shenoy and Lefkowitz, 2011). Furthermore, they play important roles in the activation of G proteinindependent signal transduction pathways, e.g.…”