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.
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We thank K. Bass, W. Zhang, S. Das, P. Hamard, L. Carvajal, B. Zhao, X. Wang, A. Chan, L.-H. Wang, S. Aaronson, and S. Muehlich for technical assistance and K. Guan for the Rheb plasmid. A.S. was supported by a research fellowship from the German Research Foundation. This study was supported by National Institutes of Health grants HL075609 (L.J.F.), CA88325 and resource grant RR17802 (R.W.), and CA095634 and GM61051 (Z.-Q.P.).