IKKepsilon-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex.
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Zhou AY, Shen RR, Kim E, Lock YJ, Xu M, Chen ZJ, Hahn WC
IKKepsilon-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex.
Cell Rep. 2013 Mar 28;3(3):724-33. doi: 10.1016/j.celrep.2013.01.031. Epub 2013 Feb 28.
- PubMed ID
- 23453969 [ View in PubMed]
- Abstract
IkappaB kinase epsilon (IKKepsilon, 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-kappaB activation. Here, we show that IKKepsilon is modified and regulated by K63-linked polyubiquitination at lysine 30 and lysine 401. Tumor necrosis factor alpha and interleukin-1beta stimulation induces IKKepsilon K63-linked polyubiquitination over baseline levels in both macrophages and breast cancer cell lines, and this modification is essential for IKKepsilon kinase activity, IKKepsilon-mediated NF-kappaB activation, and IKKepsilon-induced malignant transformation. Disruption of K63-linked ubiquitination of IKKepsilon does not affect its overall structure but impairs the recruitment of canonical NF-kappaB proteins. A cIAP1/cIAP2/TRAF2 E3 ligase complex binds to and ubiquitinates IKKepsilon. Altogether, these observations demonstrate that K63-linked polyubiquitination regulates IKKepsilon activity in both inflammatory and oncogenic contexts and suggests an alternative approach to targeting this breast cancer oncogene.