title: IKKε-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex.
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.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Alicia Y
authors: AY
authors: Zhou
authors: Rhine R
authors: RR
authors: Shen
authors: Eejung
authors: E
authors: Kim
authors: Ying J
authors: YJ
authors: Lock
authors: Ming
authors: M
authors: Xu
authors: Zhijian J
authors: ZJ
authors: Chen
authors: William C
authors: WC
authors: Hahn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase; D008239:Lysine