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

doi:10.1016/j.molcel.2008.03.009

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 language	English (US)
Pages (from-to)	403-414
Number of pages	12
Journal	Molecular Cell
Volume	30
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2008.03.009
State	Published - May 23 2008
Externally published	Yes

Bibliographical note

Funding Information:
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.).

Keywords

CELLCYCLE
HUMDISEASE
PROTEINS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "The CUL7 E3 Ubiquitin Ligase Targets Insulin Receptor Substrate 1 for Ubiquitin-Dependent Degradation",

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.",

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

note = "Funding Information: 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.). ",

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AU - Dolios, Georgia

AU - Lafontant, Pascal J.

AU - Tsai, Shih Chong

AU - Zhu, Wuqiang

AU - Nakajima, Hidehiro

AU - Nakajima, Hisako O.

AU - Field, Loren J.

AU - Wang, Rong

AU - Pan, Zhen Qiang

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

Abstract

Bibliographical note

Keywords

UN SDGs

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