Cargando…
Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of β-arrestin2
β-arrestins are well known for their roles in desensitization and sequestration of G protein–coupled receptors. Unlike β-arrestin1, β-arrestin2 exhibits a predominant cytoplasmic distribution at steady state. However, the mechanism and functional significance underlying the regulation of β-arrestin2...
Autores principales: | , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2011
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084682/ https://www.ncbi.nlm.nih.gov/pubmed/21389118 http://dx.doi.org/10.1091/mbc.E10-09-0779 |
_version_ | 1782202529989263360 |
---|---|
author | Yin, Chenlei Zhang, Ru Xu, Yongyu Chen, Qiuyan Xie, Xin |
author_facet | Yin, Chenlei Zhang, Ru Xu, Yongyu Chen, Qiuyan Xie, Xin |
author_sort | Yin, Chenlei |
collection | PubMed |
description | β-arrestins are well known for their roles in desensitization and sequestration of G protein–coupled receptors. Unlike β-arrestin1, β-arrestin2 exhibits a predominant cytoplasmic distribution at steady state. However, the mechanism and functional significance underlying the regulation of β-arrestin2 subcellular localization remains undefined. Here we report that the subcellular localization and function of β-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/β-arrestin2 complex and cause abnormal nuclear localization of β-arrestin2. Next we demonstrate that lysine residues at position 11 and 12 of β-arrestin2 are required for the interaction between Mdm2 RING finger mutant H457S (Mdm2(H457S)) and β-arrestin2, mutation of which prevents Mdm2(H457S)/β-arrestin2 interaction and subsequent nuclear localization of β-arrestin2. Finally, β-arrestin2–dependent signalings, such as receptor internalization and extracellular signal–regulated protein kinase activation, are found to be impaired once the β-arrestin2 is sequestered in the nuclei by Mdm2(H457S). Our findings depict the essential role of Mdm2 E3 ligase activity in determining β-arrestin2 subcellular localization and corresponding signaling. |
format | Text |
id | pubmed-3084682 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-30846822011-07-16 Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of β-arrestin2 Yin, Chenlei Zhang, Ru Xu, Yongyu Chen, Qiuyan Xie, Xin Mol Biol Cell Articles β-arrestins are well known for their roles in desensitization and sequestration of G protein–coupled receptors. Unlike β-arrestin1, β-arrestin2 exhibits a predominant cytoplasmic distribution at steady state. However, the mechanism and functional significance underlying the regulation of β-arrestin2 subcellular localization remains undefined. Here we report that the subcellular localization and function of β-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/β-arrestin2 complex and cause abnormal nuclear localization of β-arrestin2. Next we demonstrate that lysine residues at position 11 and 12 of β-arrestin2 are required for the interaction between Mdm2 RING finger mutant H457S (Mdm2(H457S)) and β-arrestin2, mutation of which prevents Mdm2(H457S)/β-arrestin2 interaction and subsequent nuclear localization of β-arrestin2. Finally, β-arrestin2–dependent signalings, such as receptor internalization and extracellular signal–regulated protein kinase activation, are found to be impaired once the β-arrestin2 is sequestered in the nuclei by Mdm2(H457S). Our findings depict the essential role of Mdm2 E3 ligase activity in determining β-arrestin2 subcellular localization and corresponding signaling. The American Society for Cell Biology 2011-05-01 /pmc/articles/PMC3084682/ /pubmed/21389118 http://dx.doi.org/10.1091/mbc.E10-09-0779 Text en © 2011 Yin et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,“ “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Yin, Chenlei Zhang, Ru Xu, Yongyu Chen, Qiuyan Xie, Xin Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of β-arrestin2 |
title | Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of β-arrestin2 |
title_full | Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of β-arrestin2 |
title_fullStr | Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of β-arrestin2 |
title_full_unstemmed | Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of β-arrestin2 |
title_short | Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of β-arrestin2 |
title_sort | intact mdm2 e3 ligase activity is required for the cytosolic localization and function of β-arrestin2 |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084682/ https://www.ncbi.nlm.nih.gov/pubmed/21389118 http://dx.doi.org/10.1091/mbc.E10-09-0779 |
work_keys_str_mv | AT yinchenlei intactmdm2e3ligaseactivityisrequiredforthecytosoliclocalizationandfunctionofbarrestin2 AT zhangru intactmdm2e3ligaseactivityisrequiredforthecytosoliclocalizationandfunctionofbarrestin2 AT xuyongyu intactmdm2e3ligaseactivityisrequiredforthecytosoliclocalizationandfunctionofbarrestin2 AT chenqiuyan intactmdm2e3ligaseactivityisrequiredforthecytosoliclocalizationandfunctionofbarrestin2 AT xiexin intactmdm2e3ligaseactivityisrequiredforthecytosoliclocalizationandfunctionofbarrestin2 |