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Cell Rep DOI:10.1016/j.celrep.2013.01.031

IKKε-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex.

Publication TypeJournal Article
Year of Publication2013
AuthorsZhou, AY, Shen, RR, Kim, E, Lock, YJ, Xu, M, Chen, ZJ, Hahn, WC
JournalCell Rep
Date Published2013 Mar 28
KeywordsAmino Acid Sequence, Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, I-kappa B Kinase, Inhibitor of Apoptosis Proteins, Interleukin-1beta, Lysine, Mice, Molecular Sequence Data, Neoplasms, Experimental, NF-kappa B, TNF Receptor-Associated Factor 2, Tumor Necrosis Factor-alpha, Ubiquitin-Protein Ligases, Ubiquitination

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.


Alternate JournalCell Rep
PubMed ID23453969
PubMed Central IDPMC4135466
Grant ListR01 CA130988 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States