IKKα stabilizes cytosolic β-catenin by inhibiting both canonical and non-canonical degradation pathways

β-catenin is a bi-functional protein. It is not only a major component of the cellular adhesion machinery, but is also a transcription co-activator of the Wnt signaling pathway. The cytosolic levels of the β-catenin protein, as well as its subcellular localization, are tightly regulated due to its oncogenic potentials. Two independent pathways are found to regulate β-catenin. The canonical pathway is induced by the Axin/adenomatous polyposis coli (APC)/glycogen synthase kinase-3β (GSK-3β) complex which is dependent on GSK-3β phosphorylation. The non-canonical pathway is mediated by p53-induced Siah-1 which is GSK-3β phosphorylation-independent. Recently, several studies reported that IκB kinase alpha (IKKα) could stabilize β-catenin and stimulate β-catenin/T cell factor (Tcf)-dependent transcription. Here we report that IKKα could inhibit β-catenin degradation mediated not only by the Axin/APC/GSK-3β complex, but also by the Siah-1 pathway. Consistently, we found that IKKα abolished the inhibition of β-catenin/Tcf-dependent transcription by Siah-1. Furthermore, we found that IKKα interacted with β-catenin and inhibited β-catenin ubiquitination. Taken together, our results provide a new insight into IKKα-mediated β-catenin stabilization.