Abstract
The β-arrestins (β-arrs) were initially appreciated for the roles they play in the desensitization and endocytosis of G protein-coupled receptors (GPCRs). They are now also known to act as multifunctional adaptor proteins binding many non-receptor protein partners to control multiple signalling pathways. β-arrs therefore act as key regulatory hubs at the crossroads of external cell inputs and functional outputs in cellular processes ranging from gene transcription to cell growth, survival, cytoskeletal regulation, polarity, and migration. An increasing number of studies have also highlighted the scaffolding roles β-arrs play in vivo in both physiological and pathological conditions, which opens up therapeutic avenues to explore. In this introductory review chapter, we discuss the functional roles that β-arrs exert to control GPCR function, their dynamic scaffolding roles and how this impacts signal transduction events, compartmentalization of β-arrs, how β-arrs are regulated themselves, and how the combination of these events culminates in cellular regulation.
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References
Pfister C et al (1985) Retinal S antigen identified as the 48K protein regulating light-dependent phosphodiesterase in rods. Science 228(4701):891–893
Lohse MJ et al (1990) beta-Arrestin: a protein that regulates beta-adrenergic receptor function. Science 248(4962):1547–1550
Attramadal H et al (1992) beta-Arrestin2, a novel member of the arrestin/beta-arrestin gene family. J Biol Chem 267(25):17882–17890
Tian X, Kang DS, Benovic JL (2014) beta-arrestins and G protein-coupled receptor trafficking. Handb Exp Pharmacol 219:173–186
Smith JS, Rajagopal S (2016) The beta-arrestins: multifunctional regulators of G protein-coupled receptors. J Biol Chem 291(17):8969–8977
Kang DS, Tian X, Benovic JL (2014) Role of beta-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking. Curr Opin Cell Biol 27:63–71
Aubry L, Guetta D, Klein G (2009) The arrestin fold: variations on a theme. Curr Genomics 10(2):133–142
Shenoy SK, Lefkowitz RJ (2005) Seven-transmembrane receptor signaling through beta-arrestin. Sci STKE 2005(308):cm10
Peterson YK, Luttrell LM (2017) The diverse roles of arrestin scaffolds in G protein-coupled receptor signaling. Pharmacol Rev 69(3):256–297
Xiao K et al (2007) Functional specialization of beta-arrestin interactions revealed by proteomic analysis. Proc Natl Acad Sci U S A 104(29):12011–12016
Dewire SM et al (2007) beta-arrestins and cell signaling. Annu Rev Physiol 69:483–510
Song X et al (2006) Visual and both non-visual arrestins in their "inactive" conformation bind JNK3 and Mdm2 and relocalize them from the nucleus to the cytoplasm. J Biol Chem 281(30):21491–21499
Chen Q, Iverson TM, Gurevich VV (2018) Structural basis of arrestin-dependent signal transduction. Trends Biochem Sci 43(6):412–423
Enslen H, Lima-Fernandes E, Scott MG (2014) Arrestins as regulatory hubs in cancer signalling pathways. Handb Exp Pharmacol 219:405–425
Shukla AK, Xiao K, Lefkowitz RJ (2011) Emerging paradigms of beta-arrestin-dependent seven transmembrane receptor signaling. Trends Biochem Sci 36(9):457–469
Crepieux P et al (2017) A comprehensive view of the beta-arrestinome. Front Endocrinol 8:32
Hauser AS et al (2017) Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov 16(12):829–842
Sriram K, Insel PA (2018) G protein-coupled receptors as targets for approved drugs: how many targets and how many drugs? Mol Pharmacol 93(4):251–258
Pitcher JA, Freedman NJ, Lefkowitz RJ (1998) G protein-coupled receptor kinases. Annu Rev Biochem 67:653–692
Gurevich EV et al (2012) G protein-coupled receptor kinases: more than just kinases and not only for GPCRs. Pharmacol Ther 133(1):40–69
Benovic JL et al (1987) Functional desensitization of the isolated ß-adrenergic receptor by the ß-receptor kinase: potential role of an analog of the retinal protein arrestin (48-kDa protein). Proc Natl Aca Sci U S A 84:8879–8882
Goodman OBJ et al (1996) ß-arrestin acts as a clathrin adaptor in endocytosis of the ß2-adrenergic receptor. Nature 383:447–450
Laporte SA et al (1999) The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin adaptor AP-2 during endocytosis. Proc Natl Acad Sci U S A 96(7):3712–3717
Claing A et al (2001) beta-Arrestin-mediated ADP-ribosylation factor 6 activation and beta 2-adrenergic receptor endocytosis. J Biol Chem 276(45):42509–42513
Oakley RH et al (2000) Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G protein-coupled receptors delineate two major classes of receptors. J Biol Chem 275(22):17201–17210
Oakley RH et al (2001) Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis*. J Biol Chem 276(22):19452–19460
Shenoy SK (2014) Arrestin interaction with E3 ubiquitin ligases and deubiquitinases: functional and therapeutic implications. Handb Exp Pharmacol 219:187–203
Shenoy SK, Lefkowitz RJ (2003) Trafficking patterns of beta-arrestin and G protein-coupled receptors determined by the kinetics of beta-arrestin deubiquitination. J Biol Chem 278:14498–14506
Shenoy SK et al (2009) Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2. Proc Natl Acad Sci U S A 106(16):6650–6655
Shenoy SK et al (2008) Nedd4 mediates agonist-dependent ubiquitination, lysosomal targeting, and degradation of the beta2-adrenergic receptor. J Biol Chem 283(32):22166–22176
Bhandari D et al (2007) Arrestin-2 interacts with the ubiquitin-protein isopeptide ligase atrophin-interacting protein 4 and mediates endosomal sorting of the chemokine receptor CXCR4. J Biol Chem 282(51):36971–36979
Gavard J, Gutkind JS (2006) VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 8(11):1223–1234
Shukla AK et al (2010) Arresting a transient receptor potential (TRP) channel: beta-arrestin 1 mediates ubiquitination and functional down-regulation of TRPV4. J Biol Chem 285(39):30115–30125
Chen W et al (2003) Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling. Science 301(5638):1394–1397
McDonald PH et al (2000) Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290(5496):1574–1577
Scott MG et al (2006) Cooperative regulation of ERK activation and cell shape change by Filamin A and ß-arrestins. Mol Cell Biol 26:3432–3445
DeFea KA (2011) Beta-arrestins as regulators of signal termination and transduction: how do they determine what to scaffold? Cell Signal 23(4):621–629
Cameron RT, Baillie GS (2014) Arrestin regulation of small GTPases. Handb Exp Pharmacol 219:375–385
McGovern KW, DeFea KA (2014) Molecular mechanisms underlying beta-arrestin-dependent chemotaxis and actin-cytoskeletal reorganization. Handb Exp Pharmacol 219:341–359
Chavkin C, Schattauer SS, Levin JR (2014) Arrestin-mediated activation of p38 MAPK: molecular mechanisms and behavioral consequences. Handb Exp Pharmacol 219:281–292
Zhan X et al (2014) Arrestin-dependent activation of JNK family kinases. Handb Exp Pharmacol 219:259–280
Strungs EG, Luttrell LM (2014) Arrestin-dependent activation of ERK and Src family kinases. Handb Exp Pharmacol 219:225–257
Chen Q et al (2014) Self-association of arrestin family members. Handb Exp Pharmacol 219:205–223
Gurevich VV, Gurevich EV (2014) Extensive shape shifting underlies functional versatility of arrestins. Curr Opin Cell Biol 27:1–9
Kirchhausen T, Owen D, Harrison SC (2014) Molecular structure, function, and dynamics of clathrin-mediated membrane traffic. Cold Spring Harb Perspect Biol 6(5):a016725
Krupnick JG et al (1997) Arrestin/clathrin interaction. Localization of the clathrin binding domain of nonvisual arrestins to the carboxy terminus. J Biol Chem 272(23):15011–15016
Owen DJ, Collins BM, Evans PR (2004) Adaptors for clathrin coats: structure and function. Annu Rev Cell Dev Biol 20:153–191
Kim YM, Benovic JL (2002) Differential roles of arrestin-2 interaction with clathrin and adaptor protein 2 in G protein-coupled receptor trafficking. J Biol Chem 277(34):30760–30768
Burtey A et al (2007) The conserved isoleucine-valine-phenylalanine motif couples activation state and endocytic functions of beta-arrestins. Traffic 8(7):914–931
Goodman OB Jr et al (1997) Arrestin/clathrin interaction. Localization of the arrestin binding locus to the clathrin terminal domain. J Biol Chem 272(23):15017–15022
Laporte SA et al (2000) The interaction of beta-arrestin with the AP-2 adaptor is required for the clustering of beta 2-adrenergic receptor into clathrin-coated pits. J Biol Chem 275(30):23120–23126
Schmid EM et al (2006) Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly. PLoS Biol 4(9):e262
Edeling MA et al (2006) Molecular switches involving the AP-2 beta2 appendage regulate endocytic cargo selection and clathrin coat assembly. Dev Cell 10(3):329–342
Laporte SA et al (2002) {beta}-arrestin/AP-2 interaction in GPCR internalization: Identification of a {beta}-arrestin binding site in {beta}2-adaptin. J Biol Chem 2:2
Beautrait A et al (2017) A new inhibitor of the beta-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling. Nat Commun 8:15054
Marion S et al (2007) N-terminal tyrosine modulation of the endocytic adaptor function of the beta-arrestins. J Biol Chem 282(26):18937–18944
Macia E et al (2012) Arf6 negatively controls the rapid recycling of the beta2 adrenergic receptor. J Cell Sci 125(Pt 17):4026–4035
Poupart ME et al (2007) ARF6 regulates angiotensin II type 1 receptor endocytosis by controlling the recruitment of AP-2 and clathrin. Cell Signal 19(11):2370–2378
Paleotti O et al (2005) The small G-protein Arf6GTP recruits the AP-2 adaptor complex to membranes. J Biol Chem 280(22):21661–21666
Luttrell LM et al (1999) Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science 283(5402):655–661
DeFea KA et al (2000) The proliferative and antiapoptotic effects of substance P are facilitated by formation of a beta -arrestin-dependent scaffolding complex. Proc Natl Acad Sci U S A 97(20):11086–11091
Buchanan FG et al (2006) Role of beta-arrestin 1 in the metastatic progression of colorectal cancer. Proc Natl Acad Sci U S A 103(5):1492–1497
Miller WE et al (2000) beta-arrestin1 interacts with the catalytic domain of the tyrosine kinase c-SRC. Role of beta-arrestin1-dependent targeting of c-SRC in receptor endocytosis. J Biol Chem 275(15):11312–11319
Fessart D et al (2007) Src-dependent phosphorylation of beta2-adaptin dissociates the beta-arrestin-AP-2 complex. J Cell Sci 120(Pt 10):1723–1732
Zimmerman B et al (2009) c-Src-mediated phosphorylation of AP-2 reveals a general mechanism for receptors internalizing through the clathrin pathway. Cell Signal 21(1):103–110
Penela P et al (2001) Beta-arrestin- and c-Src-dependent degradation of G-protein-coupled receptor kinase 2. EMBO J 20(18):5129–5138
Yang SH, Sharrocks AD, Whitmarsh AJ (2013) MAP kinase signalling cascades and transcriptional regulation. Gene 513(1):1–13
DeFea KA et al (2000) beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J Cell Biol 148(6):1267–1281
Luttrell LM et al (2001) Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc Natl Acad Sci U S A 98(5):2449–2454
DeWire SM et al (2008) Beta-arrestin-mediated signaling regulates protein synthesis. J Biol Chem 283(16):10611–10620
Song X et al (2009) How does arrestin assemble MAPKs into a signaling complex? J Biol Chem 284(1):685–695
Coffa S et al (2011) A single mutation in arrestin-2 prevents ERK1/2 activation by reducing c-Raf1 binding. Biochemistry 50(32):6951–6958
Meng D et al (2009) MEK1 binds directly to betaarrestin1, influencing both its phosphorylation by ERK and the timing of its isoprenaline-stimulated internalization. J Biol Chem 284(17):11425–11435
Hanson SM et al (2007) Arrestin mobilizes signaling proteins to the cytoskeleton and redirects their activity. J Mol Biol 368(2):375–387
Miller WE et al (2001) Identification of a motif in the carboxyl terminus of beta -arrestin2 responsible for activation of JNK3. J Biol Chem 276(30):27770–27777
Guo C, Whitmarsh AJ (2008) The beta-arrestin-2 scaffold protein promotes c-Jun N-terminal kinase-3 activation by binding to its nonconserved N terminus. J Biol Chem 283(23):15903–15911
Scott MG et al (2002) Differential nucleocytoplasmic shuttling of beta-arrestins. Characterization of a leucine-rich nuclear export signal in beta-arrestin2. J Biol Chem 277(40):37693–37701
Zhan X et al (2014) Arrestin-3 binds the MAP kinase JNK3alpha2 via multiple sites on both domains. Cell Signal 26(4):766–776
Zhan X et al (2016) Peptide mini-scaffold facilitates JNK3 activation in cells. Sci Rep 6:21025
Willoughby EA, Collins MK (2005) Dynamic interaction between the dual specificity phosphatase MKP7 and the JNK3 scaffold protein beta-arrestin 2. J Biol Chem 280(27):25651–25658
Sun Y et al (2002) Beta-arrestin2 is critically involved in CXCR4-mediated chemotaxis, and this is mediated by its enhancement of p38 MAPK activation. J Biol Chem 277:49212–49219
McLaughlin NJ et al (2006) Platelet-activating factor-induced clathrin-mediated endocytosis requires beta-arrestin-1 recruitment and activation of the p38 MAPK signalosome at the plasma membrane for actin bundle formation. J Immunol 176(11):7039–7050
Perry SJ et al (2002) Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins. Science 298(5594):834–836
Baillie GS et al (2007) Mapping binding sites for the PDE4D5 cAMP-specific phosphodiesterase to the N- and C-domains of beta-arrestin using spot-immobilized peptide arrays. Biochem J 404(1):71–80
Nelson CD et al (2007) Targeting of diacylglycerol degradation to M1 muscarinic receptors by beta-arrestins. Science 315(5812):663–666
Chalhoub N, Baker SJ (2009) PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 4:127–150
Povsic TJ, Kohout TA, Lefkowitz RJ (2003) Beta-arrestin1 mediates insulin-like growth factor 1 (IGF-1) activation of phosphatidylinositol 3-kinase (PI3K) and anti-apoptosis. J Biol Chem 278(51):51334–51339
Wang P et al (2007) Differential regulation of class IA phosphoinositide 3-kinase catalytic subunits p110 alpha and beta by protease-activated receptor 2 and beta-arrestins. Biochem J 408(2):221–230
Wang P, DeFea KA (2006) Protease-activated receptor-2 simultaneously directs beta-arrestin-1-dependent inhibition and Galphaq-dependent activation of phosphatidylinositol 3-kinase. Biochemistry 45(31):9374–9385
Goel R et al (2002) alpha-Thrombin induces rapid and sustained Akt phosphorylation by beta-arrestin1-dependent and -independent mechanisms, and only the sustained Akt phosphorylation is essential for G1 phase progression. J Biol Chem 277(21):18640–18648
Lodeiro M et al (2009) c-Src regulates Akt signaling in response to ghrelin via beta-arrestin signaling-independent and -dependent mechanisms. PLoS One 4(3):e4686
Luan B et al (2009) Deficiency of a beta-arrestin-2 signal complex contributes to insulin resistance. Nature 457(7233):1146–1149
Beaulieu JM et al (2005) An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122(2):261–273
Beaulieu JM et al (2008) A beta-arrestin 2 signaling complex mediates lithium action on behavior. Cell 132(1):125–136
Kendall RT et al (2011) The beta-arrestin pathway-selective type 1A angiotensin receptor (AT1A) agonist [Sar1,Ile4,Ile8]angiotensin II regulates a robust G protein-independent signaling network. J Biol Chem 286(22):19880–19891
Song MS, Salmena L, Pandolfi PP (2012) The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 13(5):283–296
Lima-Fernandes E et al (2011) Distinct functional outputs of PTEN signalling are controlled by dynamic association with beta-arrestins. EMBO J 30(13):2557–2568
Javadi A et al (2017) PTEN controls glandular morphogenesis through a juxtamembrane beta-Arrestin1/ARHGAP21 scaffolding complex. elife 6:e24578
Palmitessa A, Benovic JL (2010) Arrestin and the multi-PDZ domain-containing protein MPZ-1 interact with phosphatase and tensin homolog (PTEN) and regulate Caenorhabditis elegans longevity. J Biol Chem 285(20):15187–15200
Karin M, Lin A (2002) NF-kappaB at the crossroads of life and death. Nat Immunol 3(3):221–227
Gao H et al (2004) Identification of beta-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-kappaB pathways. Mol Cell 14(3):303–317
Witherow DS et al (2004) beta-Arrestin inhibits NF-kappaB activity by means of its interaction with the NF-kappaB inhibitor IkappaBalpha. Proc Natl Acad Sci U S A 101(23):8603–8607
Wang Y et al (2006) Association of beta-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 7(2):139–147
Sun J, Lin X (2008) Beta-arrestin 2 is required for lysophosphatidic acid-induced NF-kappaB activation. Proc Natl Acad Sci U S A 105(44):17085–17090
Hoeppner CZ, Cheng N, Ye RD (2012) Identification of a nuclear localization sequence in beta-arrestin-1 and its functional implications. J Biol Chem 287(12):8932–8943
Cianfrocca R et al (2014) beta-Arrestin 1 is required for endothelin-1-induced NF-kappaB activation in ovarian cancer cells. Life Sci 118(2):179–184
Shenoy SK et al (2001) Regulation of receptor fate by ubiquitination of activated beta 2- adrenergic receptor and beta-arrestin. Science 294(5545):1307–1313
Shenoy SK et al (2007) Ubiquitination of beta-arrestin links seven-transmembrane receptor endocytosis and ERK activation. J Biol Chem 282(40):29549–29562
Wang P et al (2003) Beta-arrestin 2 functions as a G-protein-coupled receptor-activated regulator of oncoprotein Mdm2. J Biol Chem 278(8):6363–6370
Wang P et al (2003) Subcellular localization of beta-arrestins is determined by their intact N domain and the nuclear export signal at the C terminus. J Biol Chem 278:11648–11653
Boularan C et al (2007) beta-arrestin 2 oligomerization controls the Mdm2-dependent inhibition of p53. Proc Natl Acad Sci U S A 104(46):18061–18066
Hara MR et al (2011) A stress response pathway regulates DNA damage through beta2-adrenoreceptors and beta-arrestin-1. Nature 477(7364):349–353
Kitada T et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392(6676):605–608
Ahmed MR et al (2011) Ubiquitin ligase parkin promotes Mdm2-arrestin interaction but inhibits arrestin ubiquitination. Biochemistry 50(18):3749–3763
Simonin A, Fuster D (2010) Nedd4-1 and beta-arrestin-1 are key regulators of Na+/H+ exchanger 1 ubiquitylation, endocytosis, and function. J Biol Chem 285(49):38293–38303
Bhattacharya M et al (2002) Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization. Nat Cell Biol 4(8):547–555
Li TT et al (2009) Beta-arrestin/Ral signaling regulates lysophosphatidic acid-mediated migration and invasion of human breast tumor cells. Mol Cancer Res 7(7):1064–1077
Barnes WG et al (2005) beta-Arrestin 1 and Galphaq/11 coordinately activate RhoA and stress fiber formation following receptor stimulation. J Biol Chem 280(9):8041–8050
Anthony DF et al (2011) beta-Arrestin 1 inhibits the GTPase-activating protein function of ARHGAP21, promoting activation of RhoA following angiotensin II type 1A receptor stimulation. Mol Cell Biol 31(5):1066–1075
Ma X et al (2012) Acute activation of beta2-adrenergic receptor regulates focal adhesions through betaArrestin2- and p115RhoGEF protein-mediated activation of RhoA. J Biol Chem 287(23):18925–18936
Zoudilova M et al (2007) Beta-arrestin-dependent regulation of the cofilin pathway downstream of protease-activated receptor-2. J Biol Chem 282(28):20634–20646
Zoudilova M et al (2010) beta-Arrestins scaffold cofilin with chronophin to direct localized actin filament severing and membrane protrusions downstream of protease-activated receptor-2. J Biol Chem 285(19):14318–14329
Pontrello CG et al (2012) Cofilin under control of beta-arrestin-2 in NMDA-dependent dendritic spine plasticity, long-term depression (LTD), and learning. Proc Natl Acad Sci U S A 109(7):E442–E451
Mittal N et al (2013) Select G-protein-coupled receptors modulate agonist-induced signaling via a ROCK, LIMK, and beta-arrestin 1 pathway. Cell Rep 5(4):1010–1021
Storez H et al (2005) Homo- and hetero-oligomerization of beta-arrestins in living cells. J Biol Chem 280(48):40210–40215
Kang J et al (2005) A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription. Cell 123(5):833–847
Yue R et al (2009) Beta-arrestin1 regulates zebrafish hematopoiesis through binding to YY1 and relieving polycomb group repression. Cell 139(3):535–546
Rosano L et al (2013) beta-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced beta-catenin signaling. Oncogene 32(42):5066–5077
Zhuang LN et al (2011) Beta-arrestin-1 protein represses adipogenesis and inflammatory responses through its interaction with peroxisome proliferator-activated receptor-gamma (PPARgamma). J Biol Chem 286(32):28403–28413
Purayil HT et al (2015) Arrestin2 modulates androgen receptor activation. Oncogene 34(24):3144–3151
Lakshmikanthan V et al (2009) Identification of betaArrestin2 as a corepressor of androgen receptor signaling in prostate cancer. Proc Natl Acad Sci U S A 106(23):9379–9384
Shenoy SK et al (2012) beta-arrestin1 mediates metastatic growth of breast cancer cells by facilitating HIF-1-dependent VEGF expression. Oncogene 31(3):282–292
Cianfrocca R et al (2016) Nuclear beta-arrestin1 is a critical cofactor of hypoxia-inducible factor-1alpha signaling in endothelin-1-induced ovarian tumor progression. Oncotarget 7(14):17790–17804
Zecchini V et al (2014) Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer. EMBO J 33(12):1365–1382
Gaidarov I et al (1999) Arrestin function in G protein-coupled receptor endocytosis requires phosphoinositide binding. EMBO J 18(4):871–881
Hanson SM et al (2008) Opposing effects of inositol hexakisphosphate on rod arrestin and arrestin2 self-association. Biochemistry 47(3):1070–1075
Milano SK et al (2006) Nonvisual arrestin oligomerization and cellular localization are regulated by inositol hexakisphosphate binding. J Biol Chem 81:9812–9823
Chen Q et al (2017) Structural basis of arrestin-3 activation and signaling. Nat Commun 8(1):1427
Xiao K et al (2004) Activation-dependent conformational changes in {beta}-arrestin 2. J Biol Chem 279(53):55744–55753
Nobles KN et al (2007) The active conformation of beta-arrestin1: direct evidence for the phosphate sensor in the N-domain and conformational differences in the active states of beta-arrestins1 and −2. J Biol Chem 282(29):21370–21381
Shukla AK et al (2013) Structure of active beta-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature 497(7447):137–141
Cahill TJ 3rd et al (2017) Distinct conformations of GPCR-beta-arrestin complexes mediate desensitization, signaling, and endocytosis. Proc Natl Acad Sci U S A 114(10):2562–2567
Kumari P et al (2017) Core engagement with beta-arrestin is dispensable for agonist-induced vasopressin receptor endocytosis and ERK activation. Mol Biol Cell 28(8):1003–1010
Ranjan R et al (2017) Novel Structural Insights into GPCR-beta-Arrestin Interaction and Signaling. Trends Cell Biol 27(11):851–862
Thomsen ARB et al (2016) GPCR-G protein-beta-arrestin super-complex mediates sustained G protein signaling. Cell 166(4):907–919
Charest PG, Terrillon S, Bouvier M (2005) Monitoring agonist-promoted conformational changes of beta-arrestin in living cells by intramolecular BRET. EMBO Rep 6(4):334–340
Nuber S et al (2016) beta-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle. Nature 531(7596):661–664
Lee MH et al (2016) The conformational signature of beta-arrestin2 predicts its trafficking and signalling functions. Nature 531(7596):665–668
Eichel K, Jullie D, von Zastrow M (2016) beta-Arrestin drives MAP kinase signalling from clathrin-coated structures after GPCR dissociation. Nat Cell Biol 18(3):303–310
Reiter E et al (2012) Molecular mechanism of beta-arrestin-biased agonism at seven-transmembrane receptors. Annu Rev Pharmacol Toxicol 52:179–197
Smith JS, Lefkowitz RJ, Rajagopal S (2018) Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov 17(4):243–260
Ahn S et al (2004) Differential kinetic and spatial patterns of beta-arrestin and G protein-mediated ERK activation by the angiotensin II receptor. J Biol Chem 279(34):35518–35525
Zimmerman B et al (2012) Differential beta-arrestin-dependent conformational signaling and cellular responses revealed by angiotensin analogs. Sci Signal 5(221):ra33
Violin JD et al (2010) Selectively engaging beta-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance. J Pharmacol Exp Ther 335(3):572–579
Boerrigter G et al (2011) Cardiorenal actions of TRV120027, a novel ss-arrestin-biased ligand at the angiotensin II type I receptor, in healthy and heart failure canines: a novel therapeutic strategy for acute heart failure. Circ Heart Fail 4(6):770–778
Boerrigter G et al (2012) TRV120027, a novel beta-arrestin biased ligand at the angiotensin II type I receptor, unloads the heart and maintains renal function when added to furosemide in experimental heart failure. Circ Heart Fail 5(5):627–634
Pang PS et al (2017) Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure: a randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF). Eur Heart J 38(30):2364–2373
Luttrell LM, Kenakin TP (2011) Refining efficacy: allosterism and bias in G protein-coupled receptor signaling. Methods Mol Biol 756:3–35
Whalen EJ, Rajagopal S, Lefkowitz RJ (2011) Therapeutic potential of beta-arrestin- and G protein-biased agonists. Trends Mol Med 17(3):126–139
Rankovic Z, Brust TF, Bohn LM (2016) Biased agonism: An emerging paradigm in GPCR drug discovery. Bioorg Med Chem Lett 26(2):241–250
O’Hayre M et al (2017) Genetic evidence that beta-arrestins are dispensable for the initiation of beta2-adrenergic receptor signaling to ERK. Sci Signal 10(484):eaal3395
Grundmann M et al (2018) Lack of beta-arrestin signaling in the absence of active G proteins. Nat Commun 9(1):341
Luttrell LM et al (2018) Manifold roles of beta-arrestins in GPCR signaling elucidated with siRNA and CRISPR/Cas9. Sci Signal 11(549):eaat7650
Coureuil M et al (2010) Meningococcus Hijacks a beta2-adrenoceptor/beta-Arrestin pathway to cross brain microvasculature endothelium. Cell 143(7):1149–1160
Rakesh K et al (2010) beta-Arrestin-biased agonism of the angiotensin receptor induced by mechanical stress. Sci Signal 3(125):ra46
Wu N et al (2006) Arrestin binding to calmodulin: a direct interaction between two ubiquitous signaling proteins. J Mol Biol 364(5):955–963
Scott MG et al (2002) Recruitment of activated G protein-coupled receptors to pre-existing clathrin-coated pits in living cells. J Biol Chem 277(5):3552–3559
Shenoy SK (2014) Deubiquitinases and their emerging roles in beta-arrestin-mediated signaling. Methods Enzymol 535:351–370
Tohgo A et al (2002) {beta}arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK mediated transcription following angiotensin AT1a receptor stimulation. J Biol Chem 98(change):9429–9436
Lin FT et al (1999) Feedback regulation of beta-arrestin1 function by extracellular signal-regulated kinases. J Biol Chem 274(23):15971–15974
DeFea KA (2007) Stop that cell! Beta-arrestin-dependent chemotaxis: a tale of localized actin assembly and receptor desensitization. Annu Rev Physiol 69:535–560
Ge L et al (2004) Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both beta-arrestin-1 and -2. J Biol Chem 279(53):55419–55424
Cleghorn WM et al (2015) Arrestins regulate cell spreading and motility via focal adhesion dynamics. Mol Biol Cell 26(4):622–635
Molla-Herman A et al (2008) Targeting of beta-arrestin2 to the centrosome and primary cilium: role in cell proliferation control. PLoS One 3(11):e3728
Kovacs JJ et al (2008) Beta-arrestin-mediated localization of smoothened to the primary cilium. Science 320(5884):1777–1781
Mick DU et al (2015) Proteomics of primary cilia by proximity labeling. Dev Cell 35(4):497–512
Pal K et al (2016) Smoothened determines beta-arrestin-mediated removal of the G protein-coupled receptor Gpr161 from the primary cilium. J Cell Biol 212(7):861–875
Green JA et al (2016) Recruitment of beta-arrestin into neuronal cilia modulates somatostatin receptor subtype 3 ciliary localization. Mol Cell Biol 36(1):223–235
Nager AR et al (2017) An actin network dispatches ciliary GPCRs into extracellular vesicles to modulate signaling. Cell 168(1-2):252–263 e14
Kook S et al (2014) Caspase-cleaved arrestin-2 and BID cooperatively facilitate cytochrome C release and cell death. Cell Death Differ 21(1):172–184
Oakley RH, Revollo J, Cidlowski JA (2012) Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors. Proc Natl Acad Sci U S A 109(43):17591–17596
Li J et al (2018) NF-kappaB directly regulates beta-arrestin-1 expression and forms a negative feedback circuit in TNF-alpha-induced cell death. FASEB J 32(8):4096–4106. p. fj201700642RRR
Kraemer A et al (2013) Cell survival following radiation exposure requires miR-525-3p mediated suppression of ARRB1 and TXN1. PLoS One 8(10):e77484
Wang J et al (2016) miR-365 targets beta-arrestin 2 to reverse morphine tolerance in rats. Sci Rep 6:38285
Bohn LM et al (1999) Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 286(5449):2495–2498
Sang W et al (2016) MiR-150 impairs inflammatory cytokine production by targeting ARRB-2 after blocking CD28/B7 costimulatory pathway. Immunol Lett 172:1–10
Zhao J et al (2014) beta-arrestin2/miR-155/GSK3beta regulates transition of 5′-azacytizine-induced Sca-1-positive cells to cardiomyocytes. J Cell Mol Med 18(8):1562–1570
Barthet G et al (2009) Beta-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling. EMBO J 28(18):2706–2718
Lin FT et al (2002) Phosphorylation of beta-arrestin2 regulates its function in internalization of beta(2)-adrenergic receptors. Biochemistry 41(34):10692–10699
Kim YM et al (2002) Regulation of arrestin-3 phosphorylation by casein kinase II. J Biol Chem 277(19):16837–16846
Cassier E et al (2017) Phosphorylation of beta-arrestin2 at Thr383 by MEK underlies beta-arrestin-dependent activation of Erk1/2 by GPCRs. elife 6:e23777
Paradis JS et al (2015) Receptor sequestration in response to beta-arrestin-2 phosphorylation by ERK1/2 governs steady-state levels of GPCR cell-surface expression. Proc Natl Acad Sci U S A 112(37):E5160–E5168
Khoury E et al (2014) Differential regulation of endosomal GPCR/beta-arrestin complexes and trafficking by MAPK. J Biol Chem 289(34):23302–23317
Shenoy SK, Lefkowitz RJ (2011) beta-Arrestin-mediated receptor trafficking and signal transduction. Trends Pharmacol Sci 32(9):521–533
Shenoy SK, Lefkowitz RJ (2005) Receptor-specific ubiquitination of beta-arrestin directs assembly and targeting of seven-transmembrane receptor signalosomes. J Biol Chem 280(15):15315–15324
Flotho A, Melchior F (2013) Sumoylation: a regulatory protein modification in health and disease. Annu Rev Biochem 82:357–385
Rodriguez MS, Dargemont C, Hay RT (2001) SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting. J Biol Chem 276(16):12654–12659
Wyatt D et al (2011) Small ubiquitin-like modifier modification of arrestin-3 regulates receptor trafficking. J Biol Chem 286(5):3884–3893
Xiao N et al (2015) SUMOylation attenuates human beta-arrestin 2 inhibition of IL-1R/TRAF6 signaling. J Biol Chem 290(4):1927–1935
Ozawa K et al (2008) S-nitrosylation of beta-arrestin regulates beta-adrenergic receptor trafficking. Mol Cell 31(3):395–405
Yan B et al (2011) Prolyl hydroxylase 2: a novel regulator of beta2 -adrenoceptor internalization. J Cell Mol Med 15(12):2712–2722
Min J, Defea K (2011) beta-arrestin-dependent actin reorganization: bringing the right players together at the leading edge. Mol Pharmacol 80(5):760–768
Premont RT, Gainetdinov RR (2007) Physiological roles of G protein-coupled receptor kinases and arrestins. Annu Rev Physiol 69:511–534
Schmid CL, Bohn LM (2009) Physiological and pharmacological implications of beta-arrestin regulation. Pharmacol Ther 121(3):285–293
Kohout TA et al (2001) beta-Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking. Proc Natl Acad Sci U S A 98(4):1601–1606
Zhang M et al (2011) Disruption of beta-arrestins blocks glucocorticoid receptor and severely retards lung and liver development in mice. Mech Dev 128(7-10):368–375
Bohn LM et al (2000) Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 408(6813):720–723
Raehal KM, Walker JK, Bohn LM (2005) Morphine side effects in beta-arrestin 2 knockout mice. J Pharmacol Exp Ther 314(3):1195–1201
Conner DA et al (1997) beta-Arrestin1 knockout mice appear normal but demonstrate altered cardiac responses to beta-adrenergic stimulation. Circ Res 81(6):1021–1026
Fong AM et al (2002) Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice. Proc Natl Acad Sci U S A 99(11):7478–7483
Walker JK et al (2003) Beta-arrestin-2 regulates the development of allergic asthma. J Clin Invest 112(4):566–574
Zhuang LN et al (2011) Beta-arrestin-1 protein represses diet-induced obesity. J Biol Chem 286(32):28396–28402
Ravier MA et al (2014) beta-Arrestin2 plays a key role in the modulation of the pancreatic beta cell mass in mice. Diabetologia 57(3):532–541
Zhu L et al (2017) beta-arrestin-2 is an essential regulator of pancreatic beta-cell function under physiological and pathophysiological conditions. Nat Commun 8:14295
Urs NM et al (2015) Targeting beta-arrestin2 in the treatment of L-DOPA-induced dyskinesia in Parkinson’s disease. Proc Natl Acad Sci U S A 112(19):E2517–E2526
Zou L et al (2008) Rapid xenograft tumor progression in beta-arrestin1 transgenic mice due to enhanced tumor angiogenesis. FASEB J 22(2):355–364
Raghuwanshi SK et al (2008) Depletion of beta-arrestin-2 promotes tumor growth and angiogenesis in a murine model of lung cancer. J Immunol 180(8):5699–5706
Bonnans C et al (2012) Essential requirement for beta-arrestin2 in mouse intestinal tumors with elevated Wnt signaling. Proc Natl Acad Sci U S A 109(8):3047–3052
Chaturvedi M et al (2018) Emerging paradigm of intracellular targeting of G protein-coupled receptors. Trends Biochem Sci 43(7):533–546
Acknowledgments
Work in the group of Mark G.H. Scott is supported by the Fondation ARC pour la Recherche sur le Cancer, Ligue Contre le Cancer (comité de L’Oise), France-Canada Research Foundation, the Who am I? laboratory of excellence (grant ANR-11-LABX-0071) funded by the “Investments for the Future” program operated by the French National Research Agency (grant ANR-11-IDEX-0005-01), CNRS, and INSERM. Work in the Laporte laboratory is supported by Canadian Institutes of Health Research grants (MOP-74603).
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Laporte, S.A., Scott, M.G.H. (2019). β-Arrestins: Multitask Scaffolds Orchestrating the Where and When in Cell Signalling. In: Scott, M., Laporte, S. (eds) Beta-Arrestins. Methods in Molecular Biology, vol 1957. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-9158-7_2
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