TRAF6-mediated ubiquitination of APPL1 enhances hepatic actions of insulin by promoting the membrane translocation of Akt

King Yip Cheng, Karen S.L. Lam, Yu Wang, Donghai Wu, Mingliang Zhang, Baile Wang, Xiaomu Li, Ruby L.C. Hoo, Zhe Huang, Gary Sweeney, Aimin Xu

Research output: Journal article publicationJournal articleAcademic researchpeer-review

19 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)207-216
Number of pages10
JournalBiochemical Journal
Issue number2
Publication statusPublished - 15 Oct 2013
Externally publishedYes


  • Adaptor protein
  • Gluconeogenesis
  • Insulin resistance
  • PH domain and leucine zipper containing 1 (APPL1)
  • Phosphotyrosine interaction
  • Signal transduction
  • Ubiquitination

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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