| First Author | Yin C | Year | 2011 |
| Journal | Mol Biol Cell | Volume | 22 |
| Issue | 9 | Pages | 1608-16 |
| PubMed ID | 21389118 | Mgi Jnum | J:182974 |
| Mgi Id | MGI:5317254 | Doi | 10.1091/mbc.E10-09-0779 |
| Citation | Yin C, et al. (2011) Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of beta-arrestin2. Mol Biol Cell 22(9):1608-16 |
| abstractText | beta-arrestins are well known for their roles in desensitization and sequestration of G protein-coupled receptors. Unlike beta-arrestin1, beta-arrestin2 exhibits a predominant cytoplasmic distribution at steady state. However, the mechanism and functional significance underlying the regulation of beta-arrestin2 subcellular localization remains undefined. Here we report that the subcellular localization and function of beta-arrestin2 is tightly regulated by Mdm2 E3 ligase activity. Inhibition of Mdm2 E3 ligase activity either by expressing Mdm2 RING finger mutants or using specific Mdm2 E3 ligase inhibitor is sufficient to stabilize the Mdm2/beta-arrestin2 complex and cause abnormal nuclear localization of beta-arrestin2. Next we demonstrate that lysine residues at position 11 and 12 of beta-arrestin2 are required for the interaction between Mdm2 RING finger mutant H457S (Mdm2(H457S)) and beta-arrestin2, mutation of which prevents Mdm2(H457S)/beta-arrestin2 interaction and subsequent nuclear localization of beta-arrestin2. Finally, beta-arrestin2-dependent signalings, such as receptor internalization and extracellular signal-regulated protein kinase activation, are found to be impaired once the beta-arrestin2 is sequestered in the nuclei by Mdm2(H457S). Our findings depict the essential role of Mdm2 E3 ligase activity in determining beta-arrestin2 subcellular localization and corresponding signaling. |
