b-Trcp couples b-catenin phosphorylation-degradation and regulates Xenopus axis formation

Regulation of b-catenin stability is essential for Wnt signal transduction during development and tumorigenesis. It is well known that serine-phosphorylation of b-catenin by the Axin–glycogen synthase kinase (GSK)–3b complex targets b-catenin for ubiquitination–degradation, and mutations at critical phosphoserine residues stabilize b-catenin and cause human cancers. How b-catenin phosphorylation results in its degradation is undefined. Here we show that phosphorylated b-catenin is specifically recognized by b-Trcp, an F-boxyWD40-repeat protein that also associates with Skp1, an essential component of the ubiquitination apparatus. b-catenin harboring mutations at the critical phosphoserine residues escapes recognition by b-Trcp, thus providing a molecular explanation for why these mutations cause b-catenin accumulation that leads to cancer. Inhibition of endogenous b-Trcp function by a dominant negative mutant stabilizes b-catenin, activates Wntyb-catenin signaling, and induces axis formation in Xenopus embryos. Therefore, b-Trcp plays a central role in recruiting phosphorylated b-catenin for degradation and in dorsoventral patterning of the Xenopus