IKKε-Mediated Tumorigenesis Requires K63-Linked Polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 Ubiquitin Ligase Complex

Alicia Y. Zhou, Rhine R. Shen, Eejung Kim, Ying J. Lock, Ming Xu, Zhijian J. Chen, William C. Hahn

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

IκB kinase ε (IKKε, IKBKE) is a key regulator of innate immunity and a breast cancer oncogene, amplified in ~30% of breast cancers, that promotes malignant transformation through NF-κB activation. Here, we show that IKKε is modified and regulated by K63-linked polyubiquitination at lysine 30 and lysine 401. Tumor necrosis factor alpha and interleukin-1β stimulation induces IKKε K63-linked polyubiquitination over baseline levels in both macrophages and breast cancer cell lines, and this modification is essential for IKKε kinase activity, IKKε-mediated NF-κB activation, and IKKε-induced malignant transformation. Disruption of K63-linked ubiquitination of IKKε does not affect its overall structure but impairs the recruitment of canonical NF-κB proteins. A cIAP1/cIAP2/TRAF2 E3 ligase complex binds to and ubiquitinates IKKε. Altogether, these observations demonstrate that K63-linked polyubiquitination regulates IKKε activity in both inflammatory and oncogenic contexts and suggests an alternative approach to targeting this breast cancer oncogene

Original languageEnglish (US)
Pages (from-to)724-733
Number of pages10
JournalCell Reports
Volume3
Issue number3
DOIs
StatePublished - 2013

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TNF Receptor-Associated Factor 2
Ubiquitin-Protein Ligases
Lysine
Carcinogenesis
Phosphotransferases
Chemical activation
Breast Neoplasms
Macrophages
Interleukin-1
Oncogenes
Tumor Necrosis Factor-alpha
Cells
Ubiquitination
Innate Immunity
Cell Line

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

IKKε-Mediated Tumorigenesis Requires K63-Linked Polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 Ubiquitin Ligase Complex. / Zhou, Alicia Y.; Shen, Rhine R.; Kim, Eejung; Lock, Ying J.; Xu, Ming; Chen, Zhijian J.; Hahn, William C.

In: Cell Reports, Vol. 3, No. 3, 2013, p. 724-733.

Research output: Contribution to journalArticle

Zhou, Alicia Y. ; Shen, Rhine R. ; Kim, Eejung ; Lock, Ying J. ; Xu, Ming ; Chen, Zhijian J. ; Hahn, William C. / IKKε-Mediated Tumorigenesis Requires K63-Linked Polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 Ubiquitin Ligase Complex. In: Cell Reports. 2013 ; Vol. 3, No. 3. pp. 724-733.
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