Tumorigenic Targets of IKKε

Science Signaling  20 Nov 2012:
Vol. 5, Issue 251, pp. ec300
DOI: 10.1126/scisignal.2003788

IκB kinase ε (IKKε) is a noncanonical member of the IKK family that functions as an upstream activator of the antiviral response and of the nuclear-factor κB (NF-κB)–mediated inflammatory response. The gene encoding IKKε is amplified in one-third of breast cancers. Following up on a peptide library screen and bioinformatics analysis, Shen et al. investigated the adaptor TRAF2 as a potentially cancer-relevant target of IKKε. With a combination of in vitro studies and studies mostly performed with transfected cells, they identified TRAF2 as phosphorylated on Ser11 by (IKKε), a phosphorylation event that promoted the formation of a complex (based on coimmunoprecipitation experiments) that stimulated activation of NF-κB signaling (based on reporter gene assays). Experiments with cells overexpressing tagged wild-type TRAF2 or the phosphorylation-deficient S11A mutant and IKKε indicated that phosphorylation at Ser11 promoted the Lys63-linked ubiquitylation of TRAF2. Knockdown of TRAF2 in IKKε-transformed cells reduced the activity of an NF-κB reporter and also reduced anchorage-independent colony formation, suggesting that TRAF2 was an important mediator of oncogenic signaling by IKKε. TRAF2 phosphorylation at Ser11 correlated with the abundance of IKKε in breast cancer cell lines. Additionally, knockdown of TRAF2 in the cells with increased IKKε reduced their proliferation and anchorage-independent colony formation and reduced tumor formation in a mouse xenograft model. Analysis of primary breast cancer samples showed a correlation between IKKε abundance and TRAF2 Ser11 phosphorylation, suggesting that this oncogenic pathway may be relevant to human cancers.

R. R. Shen, A. Y. Zhou, E. Kim, E. Lim, H. Habelhah, W. C. Hahn, IκB kinase ε phosphorylates TRAF2 to promote mammary epithelial cell transformation. Mol. Cell. Biol. 32, 4756–4768 (2012). [Abstract] [Full Text]