APC Is Essential for Targeting Phosphorylated β-Catenin to the SCFβ-TrCP Ubiquitin Ligase

Ubiquitin-dependent proteolysis is an important mechanism that suppresses the beta-catenin transcription factor in cells without Wnt stimulation. A critical step in this regulatory pathway is to create a SCF beta-TrCP E3 ubiquitin ligase binding site for beta-catenin. Here we show that the SCF beta-TrCP binding site created by phosphorylation of beta-catenin is highly vulnerable to protein phosphatase 2A (PP2A) and must be protected by the adenomatous polyposis coli (APC) tumor suppressor protein. Specifically, phosphorylated beta-catenin associated with the wild-type APC protein is recruited to the SCF beta-TrCP complex, ubiquitin conjugated, and degraded. A mutation in APC that deprives this protective function exposes the N-terminal phosphorylated serine/threonine residues of beta-catenin to PP2A. Dephosphorylation at these residues by PP2A eliminates the SCF beta-TrCp recognition site and blocks beta-catenin ubiquitin conjugation. Thus, by acting to protect the E3 ligase binding site, APC ensures the ubiquitin conjugation of phosphorylated beta-catenin.