Journal ArticleDOI
Regulation of Receptor Fate by Ubiquitination of Activated β2-Adrenergic Receptor and β-Arrestin
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TLDR
It is indicated that ubiquitination of the receptor and of β-arrestin have distinct and obligatory roles in the trafficking and degradation of this prototypic GPCR.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.read more
Citations
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References
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Journal ArticleDOI
The Ubiquitin System
Avram Hershko,Aaron Ciechanover +1 more
TL;DR: This review discusses recent information on functions and mechanisms of the ubiquitin system and focuses on what the authors know, and would like to know, about the mode of action of ubi...
Journal ArticleDOI
A novel genetic system to detect protein-protein interactions.
Stanley Fields,Ok-kyu Song +1 more
TL;DR: A novel genetic system to study protein-protein interactions between two proteins by taking advantage of the properties of the GAL4 protein of the yeast Saccharomyces cerevisiae, which may be applicable as a general method to identify proteins that interact with a known protein by the use of a simple galactose selection.
Journal ArticleDOI
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
TL;DR: The data suggest that the MDM2 protein, which is induced by p53, functions as a ubiquitin ligase, E3, in human papillomavirus‐uninfected cells which do not have E6 protein.
Journal ArticleDOI
The two-hybrid system: a method to identify and clone genes for proteins that interact with a protein of interest.
TL;DR: A method that detects proteins capable of interacting with a known protein and that results in the immediate availability of the cloned genes for these interacting proteins is described and could be readily extended to mammalian proteins.
Journal ArticleDOI
Beta-arrestin acts as a clathrin adaptor in endocytosis of the beta2-adrenergic receptor.
Oscar B. Goodman,Jason G. Krupnick,Francesca Santini,Vsevolod V. Gurevich,Vsevolod V. Gurevich,Raymond B. Penn,Alison W. Gagnon,James H. Keen,Jeffrey L. Benovic +8 more
TL;DR: The results show that β-arrestin functions as an adaptor in the receptor-mediated endocytosis pathway, and suggest a general mechanism for regulating the trafficking of G-protein-coupled receptors.