mTOR complex 2 regulates proper turnover of insulin receptor substrate-1 via the ubiquitin ligase subunit Fbw8

Mol Cell. 2012 Dec 28;48(6):875-87. doi: 10.1016/j.molcel.2012.09.029. Epub 2012 Nov 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Enzyme Activation
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • Gene Expression
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • Half-Life
  • Insulin / physiology
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / metabolism*
  • Phosphorylation
  • Protein Kinase C / metabolism
  • Protein Processing, Post-Translational*
  • Protein Stability
  • Proteins / metabolism
  • Proteolysis
  • Proto-Oncogene Proteins c-akt / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Signal Transduction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Carrier Proteins
  • F-Box Proteins
  • Fbxw8 protein, mouse
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Multiprotein Complexes
  • Proteins
  • stress-activated protein kinase-interacting protein, mouse
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • Protein Kinase C
  • Sirolimus