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

Abstract

Wnt signaling controls cellular development by regulating levels of {beta}-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 {beta}-catenin degradation. Mutations in APC cause deregulation of Wnt/{beta}-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 {beta}-catenin inhibition domain (CID), which is essential for {beta}-catenin destruction, but its mechanism of action is unclear. Here we find that cyclin dependent kinases and GSK3{beta} phosphorylate the CID region of APC in vitro. This allows the APC CID to bind to the E3 ubiquitin ligase component {beta}-TrCP1 in a phosphorylation dependent manner and this in turn regulates the rate of {beta}-catenin ubiquitylation. {beta} TrCP1 binding to the phosphorylated CID favors the retention and stabilization of the SCF {beta}-TrCP1 E3 ligase in the destruction complex and ensures that SCF {beta}-TrCP1 remains available for {beta}-catenin ubiquitylation. These findings provide a mechanism for the vital role of APCs CID region in {beta}-catenin destruction.