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Science 294 (5545): 1307-1313

Copyright © 2001 by the American Association for the Advancement of Science

Regulation of Receptor Fate by Ubiquitination of Activated beta 2-Adrenergic Receptor and beta -Arrestin

Sudha K. Shenoy, Patricia H. McDonald, Trudy A. Kohout, Robert J. Lefkowitz*

Although trafficking and degradation of several membrane proteins are regulated by ubiquitination catalyzed by E3 ubiquitin ligases, there has been little evidence connecting ubiquitination with regulation of mammalian G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) function. Agonist stimulation of endogenous or transfected beta 2-adrenergic receptors (beta 2ARs) led to rapid ubiquitination of both the receptors and the receptor regulatory protein, beta -arrestin. Moreover, proteasome inhibitors reduced receptor internalization and degradation, thus implicating a role for the ubiquitination machinery in the trafficking of the beta 2AR. Receptor ubiquitination required beta -arrestin, which bound to the E3 ubiquitin ligase Mdm2. Abrogation of beta -arrestin ubiquitination, either by expression in Mdm2-null cells or by dominant-negative forms of Mdm2 lacking E3 ligase activity, inhibited receptor internalization with marginal effects on receptor degradation. However, a beta 2AR mutant lacking lysine residues, which was not ubiquitinated, was internalized normally but was degraded ineffectively. These findings delineate an adapter role of beta -arrestin in mediating the ubiquitination of the beta 2AR and indicate that ubiquitination of the receptor and of beta -arrestin have distinct and obligatory roles in the trafficking and degradation of this prototypic GPCR.

Howard Hughes Medical Institute and Departments of Medicine, Cardiology and Biochemistry, Duke University Medical Center, Box 3821, Durham, NC 27710, USA.
*   To whom correspondence should be addressed: E-mail: lefko001{at}receptor-biol.duke.edu

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Differential effects of beta-arrestins on the internalization, desensitization and ERK1/2 activation downstream of protease activated receptor-2.
P. Kumar, C. S. Lau, M. Mathur, P. Wang, and K. A. DeFea (2007)
Am J Physiol Cell Physiol 293, C346-C357
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Ubiquitination differentially regulates clathrin-dependent internalization of protease-activated receptor-1.
B. L. Wolfe, A. Marchese, and J. Trejo (2007)
J. Cell Biol. 177, 905-916
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Proteasome-Regulated ERBB2 and Estrogen Receptor Pathways in Breast Cancer.
C. Marx, C. Yau, S. Banwait, Y. Zhou, G. K. Scott, B. Hann, J. W. Park, and C. C. Benz (2007)
Mol. Pharmacol. 71, 1525-1534
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Extracellular signal-regulated kinase pathway is differentially involved in beta-agonist-induced hypertrophy in slow and fast muscles.
H. Shi, C. Zeng, A. Ricome, K. M. Hannon, A. L. Grant, and D. E. Gerrard (2007)
Am J Physiol Cell Physiol 292, C1681-C1689
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Seven-Transmembrane Receptors and Ubiquitination.
S. K. Shenoy (2007)
Circ. Res. 100, 1142-1154
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Post-endocytic Sorting of Calcitonin Receptor-like Receptor and Receptor Activity-modifying Protein 1.
G. S. Cottrell, B. Padilla, S. Pikios, D. Roosterman, M. Steinhoff, E. F. Grady, and N. W. Bunnett (2007)
J. Biol. Chem. 282, 12260-12271
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beta-Arrestin and Mdm2 Mediate IGF-1 Receptor-stimulated ERK Activation and Cell Cycle Progression.
L. Girnita, S. K. Shenoy, B. Sehat, R. Vasilcanu, D. Vasilcanu, A. Girnita, R. J. Lefkowitz, and O. Larsson (2007)
J. Biol. Chem. 282, 11329-11338
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Novel insights in somatostatin receptor physiology.
G. Tulipano and S. Schulz (2007)
Eur. J. Endocrinol. 156, S3-S11
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Immunosuppressive and Anti-angiogenic Sphingosine 1-Phosphate Receptor-1 Agonists Induce Ubiquitinylation and Proteasomal Degradation of the Receptor.
M. L. Oo, S. Thangada, M.-T. Wu, C. H. Liu, T. L. Macdonald, K. R. Lynch, C.-Y. Lin, and T. Hla (2007)
J. Biol. Chem. 282, 9082-9089
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Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer.
P. Arora, T. K. Ricks, and J. Trejo (2007)
J. Cell Sci. 120, 921-928
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Mapping Pathways Downstream of Sphingosine 1-Phosphate Subtype 1 by Differential Chemical Perturbation and Proteomics.
P. J. Gonzalez-Cabrera, T. Hla, and H. Rosen (2007)
J. Biol. Chem. 282, 7254-7264
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Emerging Roles for Ubiquitin and Protein Degradation in Neuronal Function.
J. J. Yi and M. D. Ehlers (2007)
Pharmacol. Rev. 59, 14-39
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Inhibition of Agonist-Induced Down-Regulation of the {delta}-Opioid Receptor with a Proteasome Inhibitor Attenuates Opioid Tolerance in Human Embryonic Kidney 293 Cells.
P. N. Yadav, K. Chaturvedi, and R. D. Howells (2007)
J. Pharmacol. Exp. Ther. 320, 1186-1194
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Decoding ubiquitin sorting signals for clathrin-dependent endocytosis by CLASPs.
L. M. Traub and G. L. Lukacs (2007)
J. Cell Sci. 120, 543-553
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Pleiotropic beta-Agonist-Promoted Receptor Conformations and Signals Independent of Intrinsic Activity.
S. M. Swift, M. R. Schwarb, K. A. Mihlbachler, and S. B. Liggett (2007)
36, 236-243
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