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

Research output: Contribution to journal › Article › peer-review

194 Scopus citations

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

Publisher link

10.1016/j.molcel.2008.03.009

Find It

Find It at U of M Libraries

Cite this

@article{57d441ed78214a2b882da35e52e5af82,

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.",

keywords = "CELLCYCLE, HUMDISEASE, PROTEINS",

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.). ",

year = "2008",

month = may,

day = "23",

doi = "10.1016/j.molcel.2008.03.009",

language = "English (US)",

volume = "30",

pages = "403--414",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "4",

}

TY - JOUR

T1 - The CUL7 E3 Ubiquitin Ligase Targets Insulin Receptor Substrate 1 for Ubiquitin-Dependent Degradation

AU - Xu, Xinsong

AU - Sarikas, Antonio

AU - Dias-Santagata, Dora C.

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

N1 - 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.).

PY - 2008/5/23

Y1 - 2008/5/23

N2 - 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.

AB - 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.

KW - CELLCYCLE

KW - HUMDISEASE

KW - PROTEINS

UR - https://www.scopus.com/pages/publications/43449092174

UR - https://www.scopus.com/pages/publications/43449092174#tab=citedBy

U2 - 10.1016/j.molcel.2008.03.009

DO - 10.1016/j.molcel.2008.03.009

M3 - Article

C2 - 18498745

AN - SCOPUS:43449092174

SN - 1097-2765

VL - 30

SP - 403

EP - 414

JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -

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

Abstract

Bibliographical note

Keywords

Publisher link

Find It

Other files and links

Fingerprint

Cite this