β-Arrestin-mediated Receptor Trafficking and Signal Transduction

Overview

Journal Trends Pharmacol Sci

Specialty Pharmacology

Date 2011 Jun 18

PMID 21680031

Citations 338

Authors

Sudha K Shenoy

Robert J Lefkowitz

Affiliations

Soon will be listed here.

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 post-translational modifications of β-arrestins probably 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. In this review paper, we assess the traditional and novel functions of β-arrestins and discuss the molecular attributes that might facilitate multiple interactions in regulating cell signaling and receptor trafficking.

Citing Articles

Biased Opioid Receptor Agonists: Balancing Analgesic Efficacy and Side-Effect Profiles.

Ju J, Li Z, Liu J, Peng X, Gao F Int J Mol Sci. 2025; 26(5).

PMID: 40076488 PMC: 11899445. DOI: 10.3390/ijms26051862.

Development of Novel Neuroprotective Agents Targeting GPCR Using in Vitro Assays.

Gomez-Canas M, Rodriguez-Cueto C, Fernandez-Ruiz J, de Lago E Methods Mol Biol. 2025; 2899:339-366.

PMID: 40067634 DOI: 10.1007/978-1-0716-4386-0_22.

Fast-diffusing receptor collisions with slow-diffusing peptide ligand assemble the ternary parathyroid hormone-GPCR-arrestin complex.

Pacheco J, Pena K, Savransky S, Gidon A, Hammond G, Janetzko J Nat Commun. 2024; 15(1):10499.

PMID: 39627206 PMC: 11615292. DOI: 10.1038/s41467-024-54772-3.

High-affinity ELR+ chemokine ligands show G protein bias over β-arrestin recruitment and receptor internalization in CXCR1 signaling.

Boon K, Vanalken N, Szpakowska M, Chevigne A, Schols D, Loy T J Biol Chem. 2024; 301(1):108044.

PMID: 39615686 PMC: 11732455. DOI: 10.1016/j.jbc.2024.108044.

VPS26 Moonlights as a β-Arrestin-like Adapter for a 7-Transmembrane RGS Protein in .

Lou F, Zhou W, Tunc-Ozdemir M, Yang J, Velazhahan V, Tate C Biochemistry. 2024; 63(22):2990-2999.

PMID: 39467170 PMC: 11580166. DOI: 10.1021/acs.biochem.4c00361.

References

Shenoy S . Seven-transmembrane receptors and ubiquitination. Circ Res. 2007; 100(8):1142-54. PMC: 1952537. DOI: 10.1161/01.RES.0000261939.88744.5a. View

Shenoy S, Modi A, Shukla A, Xiao K, Berthouze M, Ahn S . 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. 2009; 106(16):6650-5. PMC: 2667797. DOI: 10.1073/pnas.0901083106. View

Chen W, Ren X, Nelson C, Barak L, Chen J, Beachy P . Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2. Science. 2004; 306(5705):2257-60. DOI: 10.1126/science.1104135. View

Perry S, Baillie G, Kohout T, McPhee I, Magiera M, Ang K . Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins. Science. 2002; 298(5594):834-6. DOI: 10.1126/science.1074683. View

Yamaki K, Takahashi Y, Sakuragi S, Matsubara K . Molecular cloning of the S-antigen cDNA from bovine retina. Biochem Biophys Res Commun. 1987; 142(3):904-10. DOI: 10.1016/0006-291x(87)91499-9. View

Hislop J, Von Zastrow M . Role of ubiquitination in endocytic trafficking of G-protein-coupled receptors. Traffic. 2010; 12(2):137-48. PMC: 3625703. DOI: 10.1111/j.1600-0854.2010.01121.x. View

Benovic J, Kuhn H, Weyand I, CODINA J, Caron M, Lefkowitz R . Functional desensitization of the isolated beta-adrenergic receptor by the beta-adrenergic receptor kinase: potential role of an analog of the retinal protein arrestin (48-kDa protein). Proc Natl Acad Sci U S A. 1987; 84(24):8879-82. PMC: 299654. DOI: 10.1073/pnas.84.24.8879. View

Wise A, Gearing K, Rees S . Target validation of G-protein coupled receptors. Drug Discov Today. 2002; 7(4):235-46. DOI: 10.1016/s1359-6446(01)02131-6. View

Ferguson S, Downey 3rd W, Colapietro A, Barak L, Menard L, Caron M . Role of beta-arrestin in mediating agonist-promoted G protein-coupled receptor internalization. Science. 1996; 271(5247):363-6. DOI: 10.1126/science.271.5247.363. View

10.

Mukherjee A, Veraksa A, Bauer A, Rosse C, Camonis J, Artavanis-Tsakonas S . Regulation of Notch signalling by non-visual beta-arrestin. Nat Cell Biol. 2005; 7(12):1191-201. DOI: 10.1038/ncb1327. View

11.

Oakley R, Laporte S, Holt J, Barak L, Caron M . Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis*. J Biol Chem. 2001; 276(22):19452-60. DOI: 10.1074/jbc.M101450200. View

12.

Neves S, Ram P, Iyengar R . G protein pathways. Science. 2002; 296(5573):1636-9. DOI: 10.1126/science.1071550. View

13.

Murphy J, Padilla B, Hasdemir B, Cottrell G, Bunnett N . Endosomes: a legitimate platform for the signaling train. Proc Natl Acad Sci U S A. 2009; 106(42):17615-22. PMC: 2764915. DOI: 10.1073/pnas.0906541106. View

14.

Brown M, Kovanen P, Goldstein J . Receptor-mediated uptake of lipoprotein-cholesterol and its utilization for steroid synthesis in the adrenal cortex. Recent Prog Horm Res. 1979; 35:215-57. DOI: 10.1016/b978-0-12-571135-7.50009-6. View

15.

Johnson E . Protein modification by SUMO. Annu Rev Biochem. 2004; 73:355-82. DOI: 10.1146/annurev.biochem.73.011303.074118. View

16.

Shenoy S, Lefkowitz R . Receptor-specific ubiquitination of beta-arrestin directs assembly and targeting of seven-transmembrane receptor signalosomes. J Biol Chem. 2005; 280(15):15315-24. DOI: 10.1074/jbc.M412418200. View

17.

Meloni A, Fralish G, Kelly P, Salahpour A, Chen J, Wechsler-Reya R . Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2. Mol Cell Biol. 2006; 26(20):7550-60. PMC: 1636865. DOI: 10.1128/MCB.00546-06. View

18.

Lakshmikanthan V, Zou L, Kim J, Michal A, Nie Z, Messias N . Identification of betaArrestin2 as a corepressor of androgen receptor signaling in prostate cancer. Proc Natl Acad Sci U S A. 2009; 106(23):9379-84. PMC: 2695075. DOI: 10.1073/pnas.0900258106. View

19.

Marchese A, Paing M, Temple B, Trejo J . G protein-coupled receptor sorting to endosomes and lysosomes. Annu Rev Pharmacol Toxicol. 2007; 48:601-29. PMC: 2869288. DOI: 10.1146/annurev.pharmtox.48.113006.094646. View

20.

Nakamura K, Liu X, Ascoli M . Seven non-contiguous intracellular residues of the lutropin/choriogonadotropin receptor dictate the rate of agonist-induced internalization and its sensitivity to non-visual arrestins. J Biol Chem. 2000; 275(1):241-7. DOI: 10.1074/jbc.275.1.241. View