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

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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Cell Aging, Cell Line, Cullin Proteins, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, F-Box Proteins, Humans, Insulin Receptor Substrate Proteins, Mice, Mice, Knockout, Phenotype, Protein Kinases, RNA, Small Interfering, Recombinant Fusion Proteins, Signal Transduction, TOR Serine-Threonine Kinases, Ubiquitin
Mol. Cell
Date: May. 23, 2008
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