Fig. 3.

Mechanisms contributing to the oncogenic potential of IKKɛ.

Overexpression of IKKɛ in tumor cells induces cell survival, cell transformation and proliferation by different mechanisms involving IKKɛ mediated phosphorylation of specific substrates. IKKɛ can either directly or indirectly (via Akt phosphorylation and activation) phosphorylate NF-κB (p65), leading to increased NF-κB dependent gene expression. IKKɛ also phosphorylates and inactivates the tumor suppressor CYLD, preventing CYLD from deubiquitinating specific substrates in the NF-κB signaling pathway. In addition, phosphorylation of TRAF2 activates its E3 ubiquitin ligase activity. Both CYLD and TRAF2 phosphorylation thus increase ubiquitin-dependent NF-κB signaling. IKKɛ also directly phosphorylates STAT1, increasing its gene activating potential.