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| Regulation of receptor fate by ubiquitination of activated beta(2)-adrenergic receptor and beta-arrestin |
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| Author(s): Shenoy SK, McDonald PH, Kohout TA, Lefkowitz RJ |
| Source: SCIENCE Volume: 294 Issue: 5545 Pages: 1307-1313 Published: NOV 9 2001 |
| Times Cited: 349 References: 25 |
| 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 beta (2)-adrenergic receptors (beta (2)ARs) 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 (2)AR. 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 (2)AR mutant tacking 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 (2)AR 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Lefkowitz, RJ (reprint author), Duke Univ, Med Ctr, Howard Hughes Med Inst, Box 3821, Durham, NC 27710 USA |
Addresses:
1. Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA
2. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
3. Duke Univ, Med Ctr, Dept Cardiol, Durham, NC 27710 USA
4. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA |
| Publisher: AMER ASSOC ADVANCEMENT SCIENCE, 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: 491VF |
| ISSN: 0036-8075 |
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