β-arrestins: Traffic cops of cell signaling

Howard Hughes Medical Institute, Duke University Medical Center, DUMC Box 3821, Durham, NC 27710, USA.
Current Opinion in Cell Biology (Impact Factor: 8.47). 05/2004; 16(2):162-8. DOI: 10.1016/
Source: PubMed


Once thought to function only in the desensitization of seven membrane spanning receptors (7MSRs), the ubiquitous beta-arrestin molecules are increasingly appreciated to play important roles in the endocytosis and signaling of these receptors. These functions reflect the ability of the beta-arrestins to bind an ever-growing list of signaling and endocytic elements, often in an agonist-dependent fashion. One heavily studied system is that leading to MAP kinase activation via beta-arrestin-mediated scaffolding of these pathways in a receptor-dependent fashion. The beta-arrestins are also found to be involved in the regulation of novel receptor systems, such as Frizzled and TGFbeta receptors.

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Available from: Erin Whalen, Sep 30, 2015
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    • "In the fi rst 5 min of spontaneous activity in the open fi eld arena, fl ies show intensive exploration of a novel environment , with crucial role of Kurtz nonvisual arrestin in the nervous system (Liu et al. 2007). Th e krz gene encodes the only nonvisual arrestin in Drosophila (Roman et al. 2000) which is important scaff olding proteins regulating the activity of several families of cell-surface receptors (Lefkowitz and Whalen 2004). In later phase of fl ies ' activity in the open fi eld arena dopamine takes place (Bainton et al. 2000, Friggi-Grelin et al. 2003). "
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    ABSTRACT: Purpose: Extremely low frequency (ELF) magnetic fields are essential ecological factors which may induce changes in many organisms. The aim of this study was to examine the effects in Drosophila subobscura exposed for 48 h to ELF magnetic field (50 Hz, 0.5 mT) at different developmental stages. Materials and methods: Egg-first instar larvae developmental stage of D. subobscura isofemale lines was exposed to ELF magnetic field, and fitness components (developmental time, developmental dynamics, viability and sex ratio) and locomotor activity of three-day-old males and females were monitored. Also, just eclosed D. subobscura isofemale adults were exposed to ELF magnetic field and their locomotor activity was monitored just after. Results: ELF magnetic field shortens developmental time, increases viability and does not affect sex ratio of D. subobscura. No matter which developmental stage is exposed, ELF magnetic field significantly decreases locomotor activity of adult flies, but after exposure of just eclosed adults observed change lasts longer. Conclusions: Applied ELF magnetic field modifies fitness components and locomotor activity of D. subobscura. Observed effects can be attributed to the influence of magnetic field on different stages of development where the hormonal and nervous systems play important role in the control of examined parameters.
    International Journal of Radiation Biology 01/2014; 90(5). DOI:10.3109/09553002.2014.888105 · 1.69 Impact Factor
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    • "However, β-arrestins are also essential for endocytosis of receptors via clathrin-coated pits through interactions with clathrin [22] and AP-2 adaptor protein [23]. More recently, it has been shown that β-arrestins coordinate several G protein-independent GPCR signaling cascades [24]–[26]. In these cases, the β-arrestin typically serves as a molecular scaffold, assembling multiple elements of a signaling cascade at activated receptors, thereby regulating the temporal and spatial activity of the pathway. "
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    ABSTRACT: The orphan G protein-coupled receptor (GPCR) GPR3 enhances the processing of Amyloid Precursor Protein (APP) to the neurotoxic beta-amyloid (Aβ) peptide via incompletely understood mechanisms. Through overexpression and shRNA knockdown experiments in HEK293 cells, we show that β-arrestin2 (βarr2), a GPCR-interacting scaffold protein reported to bind γ-secretase, is an essential factor for GPR3-stimulated Aβ production. For a panel of GPR3 receptor mutants, the degree of stimulation of Aβ production correlates with receptor-β-arrestin binding and receptor trafficking to endocytic vesicles. However, GPR3's recruitment of βarr2 cannot be the sole explanation, because interaction with βarr2 is common to most GPCRs, whereas GPR3 is relatively unique among GPCRs in enhancing Aβ production. In addition to β-arrestin, APP is present in a complex with GPR3 and stimulation of Aβ production by GPR3 mutants correlates with their level of APP binding. Importantly, among a broader selection of GPCRs, only GPR3 and prostaglandin E receptor 2 subtype EP2 (PTGER2; another GPCR that increases Aβ production) interact with APP, and PTGER2 does so in an agonist-stimulated manner. These data indicate that a subset of GPCRs, including GPR3 and PTGER2, can associate with APP when internalized via βarr2, and thereby promote the cleavage of APP to generate Aβ.
    PLoS ONE 09/2013; 8(9):e74680. DOI:10.1371/journal.pone.0074680 · 3.23 Impact Factor
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    • "Following agonist-induced GPCR phosphorylation, β-arrestins uncouple the receptor from G protein, leading to receptor desensitization and facilitate their clathrin-mediated internalization [10]. We have recently shown that silencing the expression of β-arrestin-2 resulted in decreased C3aR desensitization and reduced agonist-induced receptor internalization [11]. "
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    ABSTRACT: Phosphorylation of G protein coupled receptors (GPCRs) by G protein coupled receptor kinases (GRKs) and the subsequent recruitment of β-arrestins are important for their desensitization. Using shRNA-mediated gene silencing strategy, we have recently shown that GRK2, GRK3 and β-arrestin-2 promote C3a receptor (C3aR) desensitization in human mast cells. We also demonstrated that β-arrestin-2 provides an inhibitory signal for NF-κB activation. C3aR possesses ten potential phosphorylation sites within its carboxyl terminus but their role on desensitization, β-arrestin recruitment and NF-κB activation has not been determined. We utilized a site directed mutagenesis approach in transfected HEK293 cells to determine the role of receptor phosphorylation on β-arrestin-2 recruitment and RBL-2H3 cells for functional studies. We found that although Ala substitution of Ser475/479, Thr480/481 residues resulted in 58±3.8% decrease in agonist-induced C3aR phosphorylation there was no change in β-arrestin-2 binding or receptor desensitization. By contrast, Ala substitution of Thr463, Ser465, Thr466 and Ser470 led to 40±1.3% decrease in agonist-induced receptor phosphorylation but this was associated with 74±2.4% decreases in β-arrestin-2 binding, significantly reduced desensitization and enhanced NF-κB activation. Combined mutation of these Ser/Thr residues along with Ser459 (mutant MT7), resulted in complete loss of receptor phosphorylation and β-arrestin-2 binding. RBL-2H3 cells expressing MT7 responded to C3a for greater Ca(2+) mobilization, degranulation and NF-κB activation when compared to the wild-type receptor. Interestingly, co-expression of MT7 with a constitutively active mutant of β-arrestin (R169E) inhibited C3a-induced degranulation by 28±2.4% and blocked NF-κB activation by 80±2.4%. This study demonstrates that although C3a causes phosphorylation of its receptor at multiple sites, Ser459, Thr463, Ser465, Thr466 and Ser470 participate in C3aR desensitization, β-arrestin-2 recruitment and inhibition of NF-κB activity. Furthermore, β-arrestin-2 inhibits C3a-induced NF-κB activation via receptor desensitization-dependent and independent pathways.
    PLoS ONE 10/2012; 7(10):e46369. DOI:10.1371/journal.pone.0046369 · 3.23 Impact Factor
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