Publication Date:
2001-10-06
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shenoy, S K -- McDonald, P H -- Kohout, T A -- Lefkowitz, R J -- HL16037/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2001 Nov 9;294(5545):1307-13. Epub 2001 Oct 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Medicine, Duke University Medical Center, Box 3821, Durham, NC 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11588219" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Arrestins/*metabolism
;
COS Cells
;
Catalysis
;
Cell Line
;
Cricetinae
;
Cricetulus
;
Cysteine Endopeptidases/metabolism
;
Humans
;
Isoproterenol/pharmacology
;
Ligases/metabolism
;
Multienzyme Complexes/antagonists & inhibitors/metabolism
;
Mutation
;
*Nuclear Proteins
;
Phosphorylation
;
Proteasome Endopeptidase Complex
;
Proto-Oncogene Proteins/metabolism
;
Proto-Oncogene Proteins c-mdm2
;
Receptors, Adrenergic, beta-2/genetics/*metabolism
;
Recombinant Proteins/metabolism
;
Transfection
;
Ubiquitin/*metabolism
;
Ubiquitin-Protein Ligases
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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