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 Field, Rong Wang, Zhen Qiang Pan

Research output: Contribution to journalArticle

132 Citations (Scopus)

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

Fingerprint

Cullin Proteins
Insulin Receptor Substrate Proteins
Ubiquitin-Protein Ligases
Ubiquitin
70-kDa Ribosomal Protein S6 Kinases
Null Lymphocytes
MAP Kinase Signaling System
Cell Aging
Somatomedins
Sirolimus
Oncogenes
Fibroblasts
Insulin
Phenotype
Growth
Proteins

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., ... 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

The CUL7 E3 Ubiquitin Ligase Targets Insulin Receptor Substrate 1 for Ubiquitin-Dependent Degradation. / Xu, Xinsong; Sarikas, Antonio; Dias-Santagata, Dora C.; Dolios, Georgia; Lafontant, Pascal J.; Tsai, Shih Chong; Zhu, Wuqiang; Nakajima, Hidehiro; Nakajima, Hisako O.; Field, Loren; Wang, Rong; Pan, Zhen Qiang.

In: Molecular Cell, Vol. 30, No. 4, 23.05.2008, p. 403-414.

Research output: Contribution to journalArticle

Xu, X, Sarikas, A, Dias-Santagata, DC, Dolios, G, Lafontant, PJ, Tsai, SC, Zhu, W, Nakajima, H, Nakajima, HO, Field, L, Wang, R & Pan, ZQ 2008, 'The CUL7 E3 Ubiquitin Ligase Targets Insulin Receptor Substrate 1 for Ubiquitin-Dependent Degradation', Molecular Cell, vol. 30, no. 4, pp. 403-414. https://doi.org/10.1016/j.molcel.2008.03.009
Xu X, Sarikas A, Dias-Santagata DC, Dolios G, Lafontant PJ, Tsai SC et al. The CUL7 E3 Ubiquitin Ligase Targets Insulin Receptor Substrate 1 for Ubiquitin-Dependent Degradation. Molecular Cell. 2008 May 23;30(4):403-414. https://doi.org/10.1016/j.molcel.2008.03.009
Xu, Xinsong ; Sarikas, Antonio ; Dias-Santagata, Dora C. ; Dolios, Georgia ; Lafontant, Pascal J. ; Tsai, Shih Chong ; Zhu, Wuqiang ; Nakajima, Hidehiro ; Nakajima, Hisako O. ; Field, Loren ; Wang, Rong ; Pan, Zhen Qiang. / The CUL7 E3 Ubiquitin Ligase Targets Insulin Receptor Substrate 1 for Ubiquitin-Dependent Degradation. In: Molecular Cell. 2008 ; Vol. 30, No. 4. pp. 403-414.
@article{2772be3c82d544b2a6113891c11a259b,
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 Loren Field and Rong Wang and Pan, {Zhen Qiang}",
year = "2008",
month = "5",
day = "23",
doi = "10.1016/j.molcel.2008.03.009",
language = "English",
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

AU - Wang, Rong

AU - Pan, Zhen Qiang

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 - http://www.scopus.com/inward/record.url?scp=43449092174&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=43449092174&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2008.03.009

DO - 10.1016/j.molcel.2008.03.009

M3 - Article

C2 - 18498745

AN - SCOPUS:43449092174

VL - 30

SP - 403

EP - 414

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 4

ER -