Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of beta-arrestin2

doi:10.1091/mbc.E10-09-0779

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	Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of beta-arrestin2
	Yin, Chenlei 1,2; Zhang, Ru 1; Xu, Yongyu 1,2; Chen, Qiuyan 1,2; Xie, Xin1,2
刊名	MOLECULAR BIOLOGY OF THE CELL
	2011-05-01
卷号	22 期号:9 页码:1608-1616
ISSN号	1059-1524
DOI	10.1091/mbc.E10-09-0779
文献子类	Article
英文摘要	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.
资助项目	Ministry of Science and Technology of China[2008DFB30150] ; National Natural Science Foundation of China[31071227] ; Shanghai Commission of Science and Technology[08410703500] ; Shanghai Commission of Science and Technology[08431910100] ; Shanghai Commission of Science and Technology[09PJ1410000] ; Shanghai Commission of Science and Technology[09DZ2260100] ; Shanghai Commission of Science and Technology[2010CB944901] ; Shanghai Commission of Science and Technology[2011CB965104] ; Roche RRDCC Basic Research Grant[00000000]
WOS关键词	NUCLEAR EXPORT SIGNAL ; BETA-ARRESTIN ; ONCOPROTEIN MDM2 ; RECEPTOR ; PROTEIN ; P53 ; UBIQUITINATION ; ACTIVATION ; TRANSCRIPTION ; TRAFFICKING
WOS研究方向	Cell Biology
语种	英语
出版者	AMER SOC CELL BIOLOGY
WOS记录号	WOS:000290023700018
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278549]
专题	国家新药筛选中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Xie, Xin
作者单位	1.Tongji Univ, Shanghai Key Lab Signaling & Dis Res, Lab Receptor Based Biomed, Sch Life Sci & Technol, Shanghai 200092, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Yin, Chenlei,Zhang, Ru,Xu, Yongyu,et al. Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of beta-arrestin2[J]. MOLECULAR BIOLOGY OF THE CELL,2011,22(9):1608-1616.
APA	Yin, Chenlei,Zhang, Ru,Xu, Yongyu,Chen, Qiuyan,&Xie, Xin.(2011).Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of beta-arrestin2.MOLECULAR BIOLOGY OF THE CELL,22(9),1608-1616.
MLA	Yin, Chenlei,et al."Intact MDM2 E3 ligase activity is required for the cytosolic localization and function of beta-arrestin2".MOLECULAR BIOLOGY OF THE CELL 22.9(2011):1608-1616.