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Mutation of the adenomatous polyposis coli (APC) tumor suppressor stabilizes β-catenin and aberrantly reactivates Wnt/β-catenin target genes in colon cancer. APC mutants in cancer frequently lack the conserved catenin inhibitory domain (CID), which is essential for β-catenin proteolysis. Here we show that the APC CID interacts with α-catenin, a Hippo signaling regulator and heterodimeric partner of β-catenin at cell:cell adherens junctions. Importantly, α-catenin promotes β-catenin ubiquitylation and proteolysis by stabilizing its association with APC and protecting the phosphodegron. Moreover, β-catenin ubiquitylation requires binding to α-catenin. Multidimensional protein identification technology (MudPIT) proteomics of multiple Wnt regulatory complexes reveals that α-catenin binds with β-catenin to LEF-1/TCF DNA-binding proteins in Wnt3a signaling cells and recruits APC in a complex with the CtBP:CoREST:LSD1 histone H3K4 demethylase to regulate transcription and β-catenin occupancy at Wnt target genes. Interestingly, tyrosine phosphorylation of α-catenin at Y177 disrupts binding to APC but not β-catenin and prevents repression of Wnt target genes in transformed cells. Chromatin immunoprecipitation studies further show that α-catenin and APC are recruited with β-catenin to Wnt response elements in human embryonic stem cells (hESCs). Knockdown of α-catenin in hESCs prevents the switch-off of Wnt/β-catenin transcription and promotes endodermal differentiation. Our findings indicate a role for α-catenin in the APC destruction complex and at Wnt target genes.

Rapid Myc protein turnover is critical for maintaining basal levels of Myc activity in normal cells and a prompt response to changing growth signals. We characterize a new Myc-interacting factor, TRPC4AP (transient receptor potential cation channel, subfamily C, member 4-associated protein)/TRUSS (tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein), which is the receptor for a DDB1 (damage-specific DNA-binding protein 1)–CUL4 (Cullin 4) E3 ligase complex for selective Myc degradation through the proteasome. TRPC4AP/TRUSS binds specifically to the Myc C terminus and promotes its ubiquitination and destruction through the recognition of evolutionarily conserved domains in the Myc N terminus. TRPC4AP/TRUSS suppresses Myc-mediated transactivation and transformation in a dose-dependent manner. Finally, we found that TRPC4AP/TRUSS expression is strongly down-regulated in most cancer cell lines, leading to Myc protein stabilization. These studies identify a novel pathway targeting Myc degradation that is suppressed in cancer cells.