IKKalpha stabilizes cytosolic beta-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 Wnt 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-3beta (GSK-3beta) complex which is dependent on GSK-3beta phosphorylation. The non-canonical pathway is mediated by p53-induced Siah-1 which is GSK-3beta phosphorylation-independent. Recently, several studies reported that IkappaB kinase alpha (IKKalpha) could stabilize beta-catenin and stimulate beta-catenin/T cell factor (Tcf)-dependent transcription. Here we report that IKKalpha could inhibit beta-catenin degradation mediated not only by the Axin/APC/GSK-3beta complex, but also by the Siah-1 pathway. Consistently, we found that IKKalpha abolished the inhibition of beta-catenin/Tcf-dependent transcription by Siah-1. Furthermore, we found that IKKalpha interacted with beta-catenin and inhibited beta-catenin ubiquitination. Taken together, our results provide a new insight into IKKalpha-mediated beta-catenin stabilization.
Carayol
Nathalie
N
Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, 1011 N. University Avenue, Ann Arbor, MI 48109-1078, USA.
Wang
Cun-Yu
CY
D000818:Animals; D060466:Axin Protein; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000502:physiology; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
D060466:Axin Protein; D003598:Cytoskeletal Proteins; D016328:NF-kappa B; C512806:NIN protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D051550:I-kappa B Kinase