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Published Online October 4, 2001
Science DOI: 10.1126/science.1063866

Research Articles

Submitted on June 27, 2001
Accepted on September 17, 2001

Regulation of Receptor Fate by Ubiquitination of Activated ß2-Adrenergic Receptor and ß-Arrestin

Sudha K. Shenoy 1, Patricia H. McDonald 1, Trudy A. Kohout 1, Robert J. Lefkowitz 1*

1 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.

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 ß2-adrenergic receptors (ß2ARs) led to rapid ubiquitination of both the receptors and the receptor regulatory protein, ß-arrestin. Moreover, proteasome inhibitors reduced receptor internalization and degradation thus implicating a role for the ubiquitination machinery in the trafficking of the ß2AR. Receptor ubiquitination required ß-arrestin, which bound to the E3 ubiquitin ligase Mdm2. Abrogation of ß-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 ß2AR mutant lacking lysine residues, which was not ubiquitinated, was internalized normally but was degraded ineffectively. These findings delineate an adapter role of ß-arrestin in mediating the ubiquitination of the ß2AR and indicate that ubiquitination of the receptor and of ß-arrestin have distinct and obligatory roles in the trafficking and degradation of this prototypic GPCR.


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{beta}-Arrestin Is Crucial for Ubiquitination and Down-regulation of the Insulin-like Growth Factor-1 Receptor by Acting as Adaptor for the MDM2 E3 Ligase.
L. Girnita, S. K. Shenoy, B. Sehat, R. Vasilcanu, A. Girnita, R. J. Lefkowitz, and O. Larsson (2005)
J. Biol. Chem. 280, 24412-24419
   Abstract »    Full Text »    PDF »
Downregulation of the vasopressin type 2 receptor after vasopressin-induced internalization: involvement of a lysosomal degradation pathway.
R. Bouley, H. Y. Lin, M. K. Raychowdhury, V. Marshansky, D. Brown, and D. A. Ausiello (2005)
Am J Physiol Cell Physiol 288, C1390-C1401
   Abstract »    Full Text »    PDF »
Internal PDZ Ligands: Novel Endocytic Recycling Motifs for G Protein-Coupled Receptors.
J. Trejo (2005)
Mol. Pharmacol. 67, 1388-1390
   Abstract »    Full Text »    PDF »
Transduction of Receptor Signals by {beta}-Arrestins.
R. J. Lefkowitz and S. K. Shenoy (2005)
Science 308, 512-517
   Abstract »    Full Text »    PDF »
c-Cbl Mediates Ubiquitination, Degradation, and Down-regulation of Human Protease-activated Receptor 2.
C. Jacob, G. S. Cottrell, D. Gehringer, F. Schmidlin, E. F. Grady, and N. W. Bunnett (2005)
J. Biol. Chem. 280, 16076-16087
   Abstract »    Full Text »    PDF »
Receptor-specific Ubiquitination of {beta}-Arrestin Directs Assembly and Targeting of Seven-transmembrane Receptor Signalosomes.
S. K. Shenoy and R. J. Lefkowitz (2005)
J. Biol. Chem. 280, 15315-15324
   Abstract »    Full Text »    PDF »
Impairment of the ubiquitin-proteasome system by truncated cardiac myosin binding protein C mutants.
A. Sarikas, L. Carrier, C. Schenke, D. Doll, J. Flavigny, K. S. Lindenberg, T. Eschenhagen, and O. Zolk (2005)
Cardiovasc Res 66, 33-44
   Abstract »    Full Text »    PDF »
Interactions of TOM1L1 with the Multivesicular Body Sorting Machinery.
R. Puertollano (2005)
J. Biol. Chem. 280, 9258-9264
   Abstract »    Full Text »    PDF »
G Protein-coupled Receptor Endocytosis in ADP-ribosylation Factor 6-depleted Cells.
T. Houndolo, P.-L. Boulay, and A. Claing (2005)
J. Biol. Chem. 280, 5598-5604
   Abstract »    Full Text »    PDF »
Regulation of p53 and MDM2 Activity by MTBP.
M. Brady, N. Vlatkovic, and M. T. Boyd (2005)
Mol. Cell. Biol. 25, 545-553
   Abstract »    Full Text »    PDF »
The Composition of the {beta}-2 Adrenergic Receptor Oligomer Affects Its Membrane Trafficking after Ligand-Induced Endocytosis.
T. T. Cao, A. Brelot, and M. von Zastrow (2005)
Mol. Pharmacol. 67, 288-297
   Abstract »    Full Text »    PDF »
A Library of 7TM Receptor C-terminal Tails: INTERACTIONS WITH THE PROPOSED POST-ENDOCYTIC SORTING PROTEINS ERM-BINDING PHOSPHOPROTEIN 50 (EBP50), N-ETHYLMALEIMIDE-SENSITIVE FACTOR (NSF), SORTING NEXIN 1 (SNX1), AND G PROTEIN-COUPLED RECEPTOR-ASSOCIATED SORTING PROTEIN (GASP).
A. Heydorn, B. P. Sondergaard, B. Ersboll, B. Holst, F. C. Nielsen, C. R. Haft, J. Whistler, and T. W. Schwartz (2004)
J. Biol. Chem. 279, 54291-54303
   Abstract »    Full Text »    PDF »


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