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Article: Traf6-mediated ubiquitination of appl1 enhances hepatic actions of insulin by promoting the membrane translocation of akt

TitleTraf6-mediated ubiquitination of appl1 enhances hepatic actions of insulin by promoting the membrane translocation of akt
Authors
KeywordsAdaptor protein
Gluconeogenesis
Insulin resistance
PH domain and leucine zipper containing 1 (APPL1)
Phosphotyrosine interaction
Signal transduction
Ubiquitination
Issue Date2013
PublisherPortland 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?
AbstractInsulin 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 Identifierhttp://hdl.handle.net/10722/189248
ISSN
2020 Impact Factor: 3.857
2015 SCImago Journal Rankings: 2.582
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorCheng, KKY-
dc.contributor.authorLam, KSL-
dc.contributor.authorWang, Y-
dc.contributor.authorWu, D-
dc.contributor.authorZhang, M-
dc.contributor.authorWang, B-
dc.contributor.authorLi, X-
dc.contributor.authorHoo, RLC-
dc.contributor.authorHuang, Z-
dc.contributor.authorSweeney, G-
dc.contributor.authorXu, A-
dc.date.accessioned2013-09-17T14:30:57Z-
dc.date.available2013-09-17T14:30:57Z-
dc.date.issued2013-
dc.identifier.citationBiochemical Journal, 2013, v. 455 n. 2, p. 207-216-
dc.identifier.issn0264-6021-
dc.identifier.urihttp://hdl.handle.net/10722/189248-
dc.description.abstractInsulin 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.languageeng-
dc.publisherPortland Press Ltd. The Journal's web site is located at http://www.biochemj.org/-
dc.relation.ispartofBiochemical Journal-
dc.subjectAdaptor protein-
dc.subjectGluconeogenesis-
dc.subjectInsulin resistance-
dc.subjectPH domain and leucine zipper containing 1 (APPL1)-
dc.subjectPhosphotyrosine interaction-
dc.subjectSignal transduction-
dc.subjectUbiquitination-
dc.subject.meshAdaptor Proteins, Signal Transducing - genetics - metabolism-
dc.subject.meshCell Membrane - metabolism-
dc.subject.meshHepatocytes - metabolism-
dc.subject.meshProto-Oncogene Proteins c-akt - metabolism-
dc.subject.meshTNF Receptor-Associated Factor 6 - genetics - metabolism-
dc.titleTraf6-mediated ubiquitination of appl1 enhances hepatic actions of insulin by promoting the membrane translocation of akt-
dc.typeArticle-
dc.identifier.emailCheng, KKY: dorncky@hkucc.hku.hk-
dc.identifier.emailLam, KSL: ksllam@hku.hk-
dc.identifier.emailWang, Y: yuwanghk@hku.hk-
dc.identifier.emailZhang, M: mlzhang@hku.hk-
dc.identifier.emailLi, X: lixiaomu@hku.hk-
dc.identifier.emailHoo, RLC: rubyhoo@hkucc.hku.hk-
dc.identifier.emailXu, A: amxu@hkucc.hku.hk-
dc.identifier.authorityCheng, KKY=rp01672-
dc.identifier.authorityLam, KSL=rp00343-
dc.identifier.authorityWang, Y=rp00239-
dc.identifier.authorityHoo, RLC=rp01334-
dc.identifier.authorityXu, A=rp00485-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1042/BJ20130760-
dc.identifier.pmid23909487-
dc.identifier.scopuseid_2-s2.0-84884787995-
dc.identifier.hkuros221757-
dc.identifier.volume455-
dc.identifier.issue2-
dc.identifier.spage207-
dc.identifier.epage216-
dc.identifier.isiWOS:000326357800008-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl0264-6021-

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