Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin.

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Shenoy, SK; McDonald, PH; Kohout, TA; Lefkowitz, RJ

Published Date

  • November 9, 2001

Published In

Volume / Issue

  • 294 / 5545

Start / End Page

  • 1307 - 1313

PubMed ID

  • 11588219

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.1063866

Language

  • eng

Conference Location

  • United States