Abstract 983: Wnt pathway activation involves inhibition of β-catenin ubiquitination within the endogenous Axin1 complex

Abstract

Abstract Degradation of cytosolic β-catenin by the APC/Axin1 Destruction Complex represents the key regulated step of the Wnt pathway. It is incompletely understood how the Axin1 complex exerts its Wnt-regulated function. We have now examined the compositional change of the endogenous Axin1 complex in HEK293T cells upon Wnt signaling. Our results demonstrate that not only phosphorylation, but also ubiquitination and proteasomal degradation of β-catenin occur within the Axin1 complex. In disagreement with current views, we find neither a disassembly of the complex, nor an inhibition of phosphorylation of Axin1-bound β-catenin upon Wnt signaling. Comparable observations are made in primary intestinal epithelium and in colorectal cancer cell lines carrying activating Wnt pathway mutations. Wnt signaling induces the loss of the dedicated E3 ligase α-TrCP from the complex, leading to complex saturation by accumulated phospho-β-catenin. Subsequently, newly synthesized β-catenin can accumulate in a free cytosolic form, travel to the nucleus and engage the TCF Wnt effector transcription factors. In contrast to current belief, the Axin complex remains compositionally intact in APC-mutant colorectal cancer. Rather, failure of β-catenin ubiquitination is the principle biochemical activating event in these malignant cells. Together we demonstrate a novel mechanism of the destruction complex for Wnt signal activation in both physiological and malignant states. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 983. doi:1538-7445.AM2012-983