Distinct roles for β‐arrestin2 and arrestin‐domain‐containing proteins in β 2 adrenergic receptor trafficking

• Published in: EMBO reports Vol. 14; no. 2; pp. 164 - 171
• Main Authors: Han, Sang‐Oh, Kommaddi, Reddy P, Shenoy, Sudha K
• Format: Journal Article
• Language: English
• Published: 04.12.2012
• ISSN: 1469-221X; 1469-3178
• DOI: 10.1038/embor.2012.187

β‐arrestin 1 and 2 (also known as arrestin 2 and 3) are homologous adaptor proteins that regulate seven‐transmembrane receptor trafficking and signalling. Other proteins with predicted ‘arrestin‐like’ structural domains but lacking sequence homology have been indicated to function like β‐arrestin in receptor regulation. We demonstrate that β‐arrestin2 is the primary adaptor that rapidly binds agonist‐activated β 2 adrenergic receptors (β 2 ARs) and promotes clathrin‐dependent internalization, E3 ligase Nedd4 recruitment and ubiquitin‐dependent lysosomal degradation of the receptor. The arrestin‐domain‐containing (ARRDC) proteins 2, 3 and 4 are secondary adaptors recruited to internalized β 2 AR–Nedd4 complexes on endosomes and do not affect the adaptor roles of β‐arrestin2. Rather, the role of ARRDC proteins is to traffic Nedd4–β 2 AR complexes to a subpopulation of early endosomes. The endocytic adaptor ß‐arrestin2 recruits the E3 ubiquitin ligase Nedd4 and arrestin‐domain‐containing proteins to form a relay team for delivering agonist‐stimulated ß2 adrenergic receptors to sorting endosomes.