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

ABSTRACT: I?B kinase ? (IKK?, 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-?B activation. Here, we show that IKK? is modified and regulated by K63-linked polyubiquitination at lysine 30 and lysine 401. Tumor necrosis factor alpha and interleukin-1? stimulation induces IKK? K63-linked polyubiquitination over baseline levels in both macrophages and breast cancer cell lines, and this modification is essential for IKK? kinase activity, IKK?-mediated NF-?B activation, and IKK?-induced malignant transformation. Disruption of K63-linked ubiquitination of IKK? does not affect its overall structure but impairs the recruitment of canonical NF-?B proteins. A cIAP1/cIAP2/TRAF2 E3 ligase complex binds to and ubiquitinates IKK?. Altogether, these observations demonstrate that K63-linked polyubiquitination regulates IKK? activity in both inflammatory and oncogenic contexts and suggests an alternative approach to targeting this breast cancer oncogene.

SUBMITTER: Zhou AY 

PROVIDER: S-EPMC4135466 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature