APC is essential for targeting phosphorylated beta-catenin to the SCFbeta-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.
Mesh Terms:
Adenomatous Polyposis Coli Protein, Animals, Binding Sites, Cell Line, Tumor, Cell Membrane, Humans, Mutation, Phosphoproteins, Phosphorylation, Protein Phosphatase 2, Protein Processing, Post-Translational, Protein Transport, SKP Cullin F-Box Protein Ligases, Substrate Specificity, Ubiquitin, Ubiquitination, Xenopus, beta Catenin, beta-Transducin Repeat-Containing Proteins
Mol. Cell
Date: Dec. 05, 2008
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