MTOR Complex 2 Regulates Proper Turnover of Insulin Receptor Substrate-1 via the Ubiquitin Ligase Subunit Fbw8

Sung Jin Kim, Michael A. DeStefano, Won Jun Oh, Chang chih Wu, Nicole M. Vega-Cotto, Monica Finlan, Dou Liu, Bing Su, Estela Jacinto

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)875-887
Number of pages13
JournalMolecular cell
Volume48
Issue number6
DOIs
StatePublished - Dec 28 2012

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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