β-Catenin Is Targeted to the APC Destruction Complex by α-Catenin

Somatic mutations of the adenomatous polyposis coli (APC) tumor suppressor gene are found in the majority of colon cancers and usually result in truncation of the APC protein. Inactivation of APC, which normally binds β-catenin and cooperates with other proteins in a destruction complex to promote β-catenin proteolysis, promotes tumorigenesis due to aberrant β-catenin stabilization and activation of WNT/β-catenin target genes. Paradoxically, mutant APC proteins often lack the catenin inhibitory domain (CID), which is required for proteasomal degradation of β-catenin, but β-catenin does not interact with the CID. Choi and colleagues performed a proteomic analysis of APC-interacting proteins and detected α-catenin, which is known to link the actin cytoskeleton to adhesion complexes and interact with β-catenin at cell–cell adherens junctions. Unexpectedly, α-catenin was found to bind the APC CID and was required for not only the interaction between β-catenin and APC but also the ubiquitination and proteolysis of β-catenin. Phosphorylation of α-catenin on tyrosine 117, which frequently occurs in transformed cells, significantly inhibited α-catenin binding to APC, suggesting that α-catenin phosphorylation may be a common way in which cancer cells upregulate β-catenin activity and raising the possibility that targeting kinases upstream of α-catenin may have the added benefit of promoting β-catenin destruction. In response to WNT signal, β-catenin recruits α-catenin to WNT/β-catenin target gene promoters. α-Catenin then recruits APC, and the two proteins cooperate to repress transcription by recruiting lysine-specific demethylase 1, reducing histone H3 lysine 4 methylation, and promoting β-catenin release at WNT/β-catenin target genes. Collectively, these findings indicate that α-catenin plays a central role in the regulation of β-catenin stability and WNT/β-catenin target gene regulation as part of the APC destruction complex and suggests that APC mutations or α-catenin phosphorylation promote β-catenin stability and transcriptional activity by disrupting the interaction between APC and α-catenin.

Choi SH, Estarás C, Moresco JJ, Yates JR 3rd, Jones KA. α-Catenin interacts with APC to regulate β-catenin proteolysis and transcriptional repression of Wnt target genes. Genes Dev 2013;24:2473–88.

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