Trends in Pharmacological Sciences
Reviewβ-arrestin-mediated receptor trafficking and signal transduction
Section snippets
Regulation of 7-transmembrane receptors (7TMRs)
β-Arrestins 1 and 2 (also known as arrestins 2 and 3) along with the visual rod (arrestin 1) and cone (arrestin 4) arrestins constitute a small family of cytosolic adaptor proteins 1, 2, 3, 4, 5. The initial discovery and cloning of β-arrestins 1 and 2 immediately followed the characterization of the visual rod arrestin [6]. The three proteins were identified as crucial mediators of desensitization of their cognate 7TMRs, namely the β2 adrenergic receptor (β2AR, for β-arrestins) and Rhodopsin
β-Arrestins and 7TMR endocytosis
An almost universal property of cell-surface receptors (including 7TMRs) is their ability to internalize upon exposure to a ligand 13, 14, 15. Many 7TMRs internalize via clathrin-coated vesicles, but other mechanisms of internalization also exist. Receptor trafficking is an intricate process that involves dynamic protein–protein interactions as well as activation or deactivation of associated proteins. Many well-characterized 7TMRs utilize β-arrestins as endocytic adaptors, but mechanisms
β-Arrestins facilitate trafficking of unconventional 7TMRs
Frizzleds (FZDs) are 7TMRs that are activated by the Wingless/Int-1 (WNT) family of secreted lipoglycoproteins. WNT/FZD signaling is important for embryonic development, generation of cell polarity, maintenance of stem cell pluripotency and its dysregulation leads to degenerative diseases and cancer. FZDs bind to phosphorylated adaptor proteins called disheveled (DVL), and activation of FZDs leads to stabilization of the transcriptional factor β-catenin, its subsequent nuclear translocation and
β-Arrestins regulate endocytosis of non7TMRs and ion channels
Although β-arrestins were identified in the context of 7TMR regulation, there is increasing evidence that they function as adaptors for diverse cell surface receptor molecules. The first example was the demonstration that β-arrestin 1 facilitates clathrin-dependent endocytosis of the insulin-like growth factor receptor (IGF-1R) [63]. β-Arrestin 2 can also bind to and enhance endocytosis of the LDL receptor via clathrin-coated vesicles and further influence lipoprotein metabolism [64].
β-Arrestins act as adaptors for ubiquitin ligases and deubiquitinases and control postendocytic sorting
Ubiquitination of cell-surface receptors has emerged as an important post-translational modification that defines the trafficking itinerary of internalized receptors 73, 74. Ubiquitination is a highly regulated process in which the C terminal glycine of Ub is appended covalently to the epsilon amino group of a lysine residue in the substrate [75]. Transfer of ubiquitin to substrate requires an enzymatic cascade involving three distinct enzyme activities: first Ub is activated by the enzyme E1,
β-Arrestin-related proteins: the α-arrestins
β-Arrestin homologs are not expressed in yeast and lower metazoans, but structurally similar β-arrestin-related proteins, called arrestin-related trafficking adaptors (ARTs) with the characteristic ‘arrestin domain’ fold, have been shown to function as E3 ligase adaptors in yeast 90, 91, 92. The yeast ARTs are localized at the late Golgi and translocate to the plasma membrane in response to chemical stress or changes in nutrients. At the membrane, they recognize and mediate ubiquitination of
β-Arrestins balance 7TMR trafficking and signal transduction and lead to physiological outcomes
Receptor internalization was originally considered a means for turning off signaling because activated receptors are sequestered away from the cell surface and cannot bind extracellular ligands. However, it is now evident that, in many cases, signal transduction persists after the receptor has internalized, especially in the initiation of β-arrestin-dependent signaling, which coincides with the early stages of receptor endocytosis. β-Arrestins 1 and 2 bind various kinases and regulatory
Molecular mechanisms regulating β-arrestin functions
β-Arrestins undergo post-translational modifications, most often in response to 7TMR stimulation (Figure 3) and, as discussed below, these molecular changes in β-arrestin could represent its activated conformation(s) and form the basis of its various functional effects in mediating receptor trafficking and signaling.
Concluding remarks
Over the past two decades our understanding about and appreciation of the multifaceted functions of β-arrestins have greatly evolved. Nonetheless, many aspects of the functional roles of β-arrestins remain poorly understood. How does β-arrestin bind the growing ensemble of interactors? How are these novel interactions choreographed during trafficking? How are the additional interactions/functions favored over its traditional roles in receptor binding? These are some outstanding questions that
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