The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation

Mol Cell. 2008 May 23;30(4):403-14. doi: 10.1016/j.molcel.2008.03.009.

Abstract

Recent genetic studies have documented a pivotal growth-regulatory role played by the Cullin 7 (CUL7) E3 ubiquitin ligase complex containing the Fbw8-substrate-targeting subunit, Skp1, and the ROC1 RING finger protein. In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities. Interestingly, while embryonic fibroblasts of Cul7-/- mice were found to accumulate IRS-1 and exhibit increased activation of IRS-1's downstream Akt and MEK/ERK pathways, these null cells grew poorly and displayed phenotypes reminiscent of those associated with oncogene-induced senescence. Taken together, our findings demonstrate a key role for the CUL7 E3 in targeting IRS-1 for degradation, a process that may contribute to the regulation of cellular senescence.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line
  • Cellular Senescence
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism*
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism
  • Humans
  • Insulin Receptor Substrate Proteins
  • Mice
  • Mice, Knockout
  • Phenotype
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases
  • Ubiquitin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cul7 protein, mouse
  • Cullin Proteins
  • F-Box Proteins
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Ubiquitin
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Extracellular Signal-Regulated MAP Kinases