The CUL7 E3 Ubiquitin Ligase Targets Insulin Receptor Substrate 1 for Ubiquitin-Dependent Degradation

Xinsong Xu, Antonio Sarikas, Dora C. Dias-Santagata, Georgia Dolios, Pascal J. Lafontant, Shih Chong Tsai, Wuqiang Zhu, Hidehiro Nakajima, Hisako O. Nakajima, Loren J. Field, Rong Wang, Zhen Qiang Pan

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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.

Original languageEnglish (US)
Pages (from-to)403-414
Number of pages12
JournalMolecular Cell
Volume30
Issue number4
DOIs
StatePublished - May 23 2008

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Keywords

  • CELLCYCLE
  • HUMDISEASE
  • PROTEINS

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Xu, X., Sarikas, A., Dias-Santagata, D. C., Dolios, G., Lafontant, P. J., Tsai, S. C., Zhu, W., Nakajima, H., Nakajima, H. O., Field, L. J., Wang, R., & Pan, Z. Q. (2008). The CUL7 E3 Ubiquitin Ligase Targets Insulin Receptor Substrate 1 for Ubiquitin-Dependent Degradation. Molecular Cell, 30(4), 403-414. https://doi.org/10.1016/j.molcel.2008.03.009