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- Title
TRAF6-mediated ubiquitination of APPL1 enhances hepatic actions of insulin by promoting the membrane translocation of Akt.
- Authors
CHENG, Kenneth K. Y.; LAM, Karen S. L.; Yu WANG; Donghai WU; Mingliang ZHANG; Baile WANG; Xiaomu LI; HOO, Ruby L. C.; Zhe HUANG; SWEENEY, Gary; Aimin XU
- Abstract
Insulin inhibits hepatic glucose production through activation of the protein kinase Akt, and any defect in this pathway causes fasting hyperglycaemia in Type 2 diabetes. APPL1 [adaptor protein, phosphotyrosine interaction, PH (pleckstrin homology) domain and leucine zipper containing 1] sensitizes hepatic insulin action on suppression of gluconeogenesis by binding to Akt. However, the mechanisms underlying the insulin-sensitizing actions of APPL1 remain elusive. In the present study we show that insulin induces Lys63-linked ubiquitination of APPL1 in primary hepatocytes and in the livers of C57 mice. Lys160 located within the BAR (Bin/amphiphysin/Rvs) domain of APPL1 is the major site for its ubiquitination. Replacement of Lys160 with arginine abolishes insulin-dependent ubiquitination and membrane localization of APPL1, and also diminishes membrane recruitment and activation of Akt, thereby abrogating the effects of APPL1 on alleviation of hepatic insulin resistance and glucose intolerance in obese mice. Further analysis identified TRAF6 (tumour-necrosis-factor-receptor-associated factor 6) as an E3 ubiquitin ligase for APPL1 ubiquitination. Suppression of TRAF6 expression attenuates insulin-mediated ubiquitination and membrane targeting of APPL1, leading to an impairment of insulinstimulated Akt activation and inhibition of gluconeogenesis in hepatocytes. Thus TRAF6-mediated ubiquitination of APPL1 is a vital step for the hepatic actions of insulin through modulation of membrane trafficking and activity of Akt.
- Subjects
UBIQUITINATION; PHYSIOLOGICAL effects of insulin; CYCLIC-AMP-dependent protein kinase; HYPERGLYCEMIA treatment; GENETICS of type 2 diabetes; PROTEIN-tyrosine phosphatase; LIVER cells
- Publication
Biochemical Journal, 2013, Vol 455, Issue 2, p207
- ISSN
0264-6021
- Publication type
Article
- DOI
10.1042/BJ20130760