Deficiency of a β-arrestin-2 signal complex contributes to insulin resistance

被引:184
作者
Luan, Bing [1 ,2 ]
Zhao, Jian [1 ,2 ]
Wu, Haiya [4 ,5 ,6 ]
Duan, Baoyu [1 ,2 ]
Shu, Guangwen [1 ,2 ]
Wang, Xiaoying [7 ]
Li, Dangsheng [3 ]
Jia, Weiping [4 ,5 ,6 ]
Kang, Jiuhong [1 ,2 ]
Pei, Gang [1 ,2 ,8 ]
机构
[1] Chinese Acad Sci, Mol Cell Biol Lab, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China
[2] Chinese Acad Sci, Grad Sch, Shanghai 200031, Peoples R China
[3] Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Informat Ctr Life Sci, Shanghai 200031, Peoples R China
[4] Shanghai Jiao Tong Univ, Dept Endocrinol & Metab, Affiliated Peoples Hosp 6, Shanghai, Peoples R China
[5] Shanghai Diabet Inst, Shanghai, Peoples R China
[6] Shanghai Clin Ctr Diabet, Shanghai 200233, Peoples R China
[7] Fudan Univ, Affiliated Zhongshan Hosp, Shanghai 200032, Peoples R China
[8] Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China
基金
中国国家自然科学基金;
关键词
PHOSPHATIDYLINOSITOL; 3-KINASE; ACTIVATION; PROTEIN; KINASE; AKT; SRC; OBESITY; PHOSPHORYLATION; TRANSDUCTION; PATHWAYS;
D O I
10.1038/nature07617
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Insulin resistance, a hallmark of type 2 diabetes, is a defect of insulin in stimulating insulin receptor signalling(1,2), which has become one of the most serious public health threats. Upon stimulation by insulin, insulin receptor recruits and phosphorylates insulin receptor substrate proteins(3), leading to activation of the phosphatidylinositol-3-OH kinase (PI(3) K)-Akt pathway. Activated Akt phosphorylates downstream kinases and transcription factors, thus mediating most of the metabolic actions of insulin(4-6). beta-arrestins mediate biological functions of G-protein-coupled receptors by linking activated receptors with distinct sets of accessory and effecter proteins, thereby determining the specificity, efficiency and capacity of signals(7-11). Here we show that in diabetic mouse models, beta-arrestin-2 is severely downregulated. Knockdown of beta-arrestin-2 exacerbates insulin resistance, whereas administration of beta-arrestin-2 restores insulin sensitivity in mice. Further investigation reveals that insulin stimulates the formation of a new beta-arrestin-2 signal complex, in which beta-arrestin-2 scaffolds Akt and Src to insulin receptor. Loss or dysfunction of beta-arrestin-2 results in deficiency of this signal complex and disturbance of insulin signalling in vivo, thereby contributing to the development of insulin resistance and progression of type 2 diabetes. Our findings provide new insight into the molecular pathogenesis of insulin resistance, and implicate new preventive and therapeutic strategies against insulin resistance and type 2 diabetes.
引用
收藏
页码:1146 / U105
页数:5
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