Phosphorylation-dependent binding of the Adenomatous Polyposis Coli protein to β-TrCP1 regulates β-catenin destruction.

Wnt signaling controls cellular development by regulating levels of β-catenin, a dual transcription factor and adhesion protein. The tumor suppressor gene Adenomatous Polyposis coli (APC) is a negative regulator of Wnt signaling that acts by interacting with multiple proteins in the destruction complex to drive β-catenin degradation. Mutations in APC cause deregulation of Wnt/β-catenin signaling contributing to the development of several types of cancer, especially colorectal cancers. Tumors are not null mutant for APC-instead they accumulate truncated proteins. Many APC proteins are truncated between the second and third 20-amino acid repeats, a region known as the β-catenin inhibition domain (CID), which is essential for β-catenin destruction, but its mechanism of action is unclear. Here we find that cyclin dependent kinases and GSK3β phosphorylate the CID region of APC in vitro. This allows the APC CID to bind to the E3 ubiquitin ligase component β-TrCP1 in a phosphorylation dependent manner and this in turn regulates the rate of β-catenin ubiquitylation. β-TrCP1 binding to the phosphorylated CID favors the retention and stabilization of the SCFβ-TrCP1 E3 ligase in the destruction complex and ensures that SCFβ-TrCP1 remains available for β-catenin ubiquitylation. These findings provide a mechanism for the vital role of APC's CID region in β-catenin destruction.