PMID:11588219

Citation	Shenoy, SK, McDonald, PH, Kohout, TA and Lefkowitz, RJ (2001) Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science 294:1307-13
Abstract	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 beta2-adrenergic receptors (beta2ARs) 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 beta2AR. 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 beta2AR 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 beta2AR 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.
Links	PubMed Online version:10.1126/science.1063866
Keywords	Animals; Arrestins/metabolism; COS Cells; Catalysis; Cell Line; Cricetinae; Cricetulus; Cysteine Endopeptidases/metabolism; Humans; Isoproterenol/pharmacology; Ligases/metabolism; Multienzyme Complexes/antagonists & inhibitors; Multienzyme Complexes/metabolism; Mutation; Nuclear Proteins; Phosphorylation; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-mdm2; Receptors, Adrenergic, beta-2/genetics; Receptors, Adrenergic, beta-2/metabolism; Recombinant Proteins/metabolism; Transfection; Ubiquitin/metabolism; Ubiquitin-Protein Ligases
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:ARRB2		GO:0031398: positive regulation of protein ubiquitination	ECO:0000314:		P		Figure 3	complete

References

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