HAT cofactor TRRAP mediates β-catenin ubiquitination on the chromatin and the regulation of the canonical Wnt pathway

Abstract

The Wnt pathway is a key regulator of embryonic development and stem cell self-renewal, and hyperactivation of the Wnt signalling is associated with many human cancers. The central player in the Wnt pathway is β-catenin, a cytoplasmic protein whose function is tightly controlled by ubiquitination and degradation, however the precise regulation of β-catenin stability/degradation remains elusive. Here, we report a new mechanism of β-catenin ubiquitination acting in the context of chromatin. This mechanism is mediated by the histone acetyltransferase (HAT) complex component TRRAP and Skp1, an invariable component of the Skp-Cullin-F-box (SCF) ubiquitin ligase complex. TRRAP interacts with Skp1/SCF and mediates its recruitment to β-catenin target promoter in chromatin. TRRAP deletion leads to a reduced level of β-catenin ubiquitination, lower degradation rate and accumulation of β-catenin protein. Furthermore, recruitment of Skp1 to chromatin and ubiquitination of chromatin-bound β-catenin are abolished upon TRRAP knock-down, leading to an abnormal retention of β-catenin at the chromatin and concomitant hyperactivation of the canonical Wnt pathway. These results demonstrate that there is a distinct regulatory mechanism for β-catenin ubiquitination/ destruction acting in the nucleus which functionally complements cytoplasmic destruction of β-catenin and prevents its oncogenic stabilization and chronic activation of the canonical Wnt pathway. ©2008 Landes Bioscience.