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- Publisher Website: 10.1042/BJ20130760
- Scopus: eid_2-s2.0-84884787995
- PMID: 23909487
- WOS: WOS:000326357800008
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Article: Traf6-mediated ubiquitination of appl1 enhances hepatic actions of insulin by promoting the membrane translocation of akt
Title | Traf6-mediated ubiquitination of appl1 enhances hepatic actions of insulin by promoting the membrane translocation of akt |
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Authors | |
Keywords | Adaptor protein Gluconeogenesis Insulin resistance PH domain and leucine zipper containing 1 (APPL1) Phosphotyrosine interaction Signal transduction Ubiquitination |
Issue Date | 2013 |
Publisher | Portland Press Ltd. The Journal's web site is located at http://www.biochemj.org/ |
Citation | Biochemical Journal, 2013, v. 455 n. 2, p. 207-216 How to Cite? |
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 insulin-stimulated 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. |
Persistent Identifier | http://hdl.handle.net/10722/189248 |
ISSN | 2023 Impact Factor: 4.4 2023 SCImago Journal Rankings: 1.612 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Cheng, KKY | - |
dc.contributor.author | Lam, KSL | - |
dc.contributor.author | Wang, Y | - |
dc.contributor.author | Wu, D | - |
dc.contributor.author | Zhang, M | - |
dc.contributor.author | Wang, B | - |
dc.contributor.author | Li, X | - |
dc.contributor.author | Hoo, RLC | - |
dc.contributor.author | Huang, Z | - |
dc.contributor.author | Sweeney, G | - |
dc.contributor.author | Xu, A | - |
dc.date.accessioned | 2013-09-17T14:30:57Z | - |
dc.date.available | 2013-09-17T14:30:57Z | - |
dc.date.issued | 2013 | - |
dc.identifier.citation | Biochemical Journal, 2013, v. 455 n. 2, p. 207-216 | - |
dc.identifier.issn | 0264-6021 | - |
dc.identifier.uri | http://hdl.handle.net/10722/189248 | - |
dc.description.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 insulin-stimulated 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. | - |
dc.language | eng | - |
dc.publisher | Portland Press Ltd. The Journal's web site is located at http://www.biochemj.org/ | - |
dc.relation.ispartof | Biochemical Journal | - |
dc.subject | Adaptor protein | - |
dc.subject | Gluconeogenesis | - |
dc.subject | Insulin resistance | - |
dc.subject | PH domain and leucine zipper containing 1 (APPL1) | - |
dc.subject | Phosphotyrosine interaction | - |
dc.subject | Signal transduction | - |
dc.subject | Ubiquitination | - |
dc.subject.mesh | Adaptor Proteins, Signal Transducing - genetics - metabolism | - |
dc.subject.mesh | Cell Membrane - metabolism | - |
dc.subject.mesh | Hepatocytes - metabolism | - |
dc.subject.mesh | Proto-Oncogene Proteins c-akt - metabolism | - |
dc.subject.mesh | TNF Receptor-Associated Factor 6 - genetics - metabolism | - |
dc.title | Traf6-mediated ubiquitination of appl1 enhances hepatic actions of insulin by promoting the membrane translocation of akt | - |
dc.type | Article | - |
dc.identifier.email | Cheng, KKY: dorncky@hkucc.hku.hk | - |
dc.identifier.email | Lam, KSL: ksllam@hku.hk | - |
dc.identifier.email | Wang, Y: yuwanghk@hku.hk | - |
dc.identifier.email | Zhang, M: mlzhang@hku.hk | - |
dc.identifier.email | Li, X: lixiaomu@hku.hk | - |
dc.identifier.email | Hoo, RLC: rubyhoo@hkucc.hku.hk | - |
dc.identifier.email | Xu, A: amxu@hkucc.hku.hk | - |
dc.identifier.authority | Cheng, KKY=rp01672 | - |
dc.identifier.authority | Lam, KSL=rp00343 | - |
dc.identifier.authority | Wang, Y=rp00239 | - |
dc.identifier.authority | Hoo, RLC=rp01334 | - |
dc.identifier.authority | Xu, A=rp00485 | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1042/BJ20130760 | - |
dc.identifier.pmid | 23909487 | - |
dc.identifier.scopus | eid_2-s2.0-84884787995 | - |
dc.identifier.hkuros | 221757 | - |
dc.identifier.volume | 455 | - |
dc.identifier.issue | 2 | - |
dc.identifier.spage | 207 | - |
dc.identifier.epage | 216 | - |
dc.identifier.isi | WOS:000326357800008 | - |
dc.publisher.place | United Kingdom | - |
dc.identifier.issnl | 0264-6021 | - |