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

Cell Rep 2013 Mar 28;3(3):724-33. Epub 2013 Feb 28.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

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.

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Source
https://linkinghub.elsevier.com/retrieve/pii/S22111247130005
Publisher Site
http://dx.doi.org/10.1016/j.celrep.2013.01.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135466PMC
March 2013
17 Citations
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