Abstract
Oxidative stress, which can cause DNA damage, can both activate TNF-R1 directly in the absence of TNF stimulation and phosphorylate c-Abl, thus promoting its cytoplasmic translocation. Persistent cytoplasmic localization of c-Abl has been associated with cellular transformation. c-Abl phosphorylates OTULIN at tyrosine 56, thereby disrupting its relationship with LUBAC. OTULIN-released LUBAC interacts with SPATA2 and is recruited to the TNF-R1sc, facilitating SPATA2-CYLD interaction. All these interactions are required for the activation of IKKβ to stimulate NF-κB transcriptional activity following genotoxic stress. IKKβ also induces the critical phosphorylation of CYLD at serine 568 to increase its deubiquitinating (DUB) activity required for the termination of signaling cascades. Contrary to the widespread belief that CYLD is an absolute tumor suppressor, CYLD initiates and terminates NF-κB activity by alternately using its oncoprotein and tumor suppressor activities, respectively. If IKKβ fails to achieve the DUB activity-inducing phosphorylation at serine 568, CYLD would operate in a sustained mode of oncogenic activity. The resulting dysregulated NF-κB activation and other accompanying pathologies will disrupt cellular homeostasis in favor of transformation.