title: mTOR complex 2 regulates proper turnover of insulin receptor substrate-1 via the ubiquitin ligase subunit Fbw8.
abstract: The mammalian target of rapamycin (mTOR) integrates signals from nutrients and insulin via two distinct complexes, mTORC1 and mTORC2. Disruption of mTORC2 impairs the insulin-induced activation of Akt, an mTORC2 substrate. Here, we found that mTORC2 can also regulate insulin signaling at the level of insulin receptor substrate-1 (IRS-1). Despite phosphorylation at the mTORC1-mediated serine sites, which supposedly triggers IRS-1 downregulation, inactive IRS-1 accumulated in mTORC2-disrupted cells. Defective IRS-1 degradation was due to attenuated expression and phosphorylation of the ubiquitin ligase substrate-targeting subunit, Fbw8. mTORC2 stabilizes Fbw8 by phosphorylation at Ser86, allowing the insulin-induced translocation of Fbw8 to the cytosol where it mediates IRS-1 degradation. Thus, mTORC2 negatively feeds back to IRS-1 via control of Fbw8 stability and localization. Our findings reveal that in addition to persistent mTORC1 signaling, heightened mTORC2 signals can promote insulin resistance due to mTORC2-mediated degradation of IRS-1.
authors.affiliation: Department of Biochemistry and Molecular Biology, UMDNJ-RWJMS, Piscataway, NJ 08854, USA.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Michael A
authors.initials: MA
authors.lastname: DeStefano
authors.forename: Won Jun
authors.initials: WJ
authors.lastname: Oh
authors.forename: Chang-chih
authors.initials: CC
authors.lastname: Wu
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Vega-Cotto
authors.forename: Monica
authors.initials: M
authors.lastname: Finlan
authors.forename: Dou
authors.initials: D
authors.lastname: Liu
authors.forename: Bing
authors.initials: B
authors.lastname: Su
authors.forename: Estela
authors.initials: E
authors.lastname: Jacinto
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006207:Half-Life; D007328:Insulin / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D011506:Proteins / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing
chemical_list: D002352:Carrier Proteins; D044783:F-Box Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D011493:Protein Kinase C; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C513332:Fbxw8 protein, mouse; C526295:Irs1 protein, mouse; C561937:Mapkap1 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; C512964:Rps6ka1 protein, mouse