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

beta-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 Writ signaling pathway. The cytosolic levels of the beta-catenin protein, as well as its subcellular localization, are tightly regulated due to its oncogenic potentials. Two independent pathways are found to regulate beta-catenin. The canonical pathway is induced by the Axin/adenomatous polyposis coli (APC)/glycogen synthase kinase-3 (GSK-3 beta) complex which is dependent on GSK-3 beta phosphorylation. The non-canonical pathway is mediated by p53-induced Siah-1 which is GSK-3 beta phosphorylation-independent. Recently, several studies reported that I kappa B kinase alpha (IKK alpha) could stabilize beta-catenin and stimulate beta-catenin/T cell factor (Tcf)-dependent transcription. Here we report that IKKa could inhibit beta-catenin degradation mediated not only by the Axin/APC/GSK-3 beta complex, but also by the Siah-1 pathway. Consistently, we found that IKK alpha abolished the inhibition of beta-catenin/Tcf-dependent transcription by Siah-1. Furthermore, we found that IKK alpha interacted with beta-catenin and inhibited beta-catenin ubiquitination. Taken together, our results provide a new insight into IKK alpha-mediated beta-catenin stabilization. (c) 2006 Elsevier Inc. All rights reserved.