Identification of ICAT as an APC inhibitor, revealing Wnt-dependent inhibition of APC-Axin interaction

Adenomatous polyposis coli (APC) and Axin are core components of the beta-catenin destruction complex. How APC’s function is regulated and whether Wnt signaling influences the direct APC-Axin interaction to inhibit the beta-catenin destruction complex and not clear. Through a CRISPR screen of beta-catenin stability, we have identified ICAT, a polypeptide previously known to block beta-catenin-TCF interaction, as a natural inhibitor of APC. ICAT blocks beta-catenin-APC interaction and prevents beta-catenin-mediated APC-Axin interaction, enhancing stabilization of beta-catenin in cells harboring truncated APC or stimulated with Wnt, but not in cells deprived of a Wnt signal. Using ICAT as a tool to disengage beta-catenin-mediated APC-Axin interaction, we demonstrate that Wnt quickly inhibits the direct interaction between APC and Axin. Our study highlights an important scaffolding function of beta-catenin in the assembly of the destruction complex and suggests Wnt-inhibited APC-Axin interaction as a novel mechanism of Wnt-dependent inhibition of the destruction complex.