APC Controls Wnt‐Induced β‐catenin Destruction Complex Recruitment in Human Colonocytes

Wnt signaling is essential for intestinal homeostasis and is aberrantly activated in the majority of colorectal cancers (CRC). In over 80% of CRC, the tumor suppressor Adenomatous Polyposis Coli (APC) is mutated, resulting in expression of a truncated protein product. APC is a key component of the β‐catenin destruction complex, which maintains low cellular levels of β‐catenin but is inhibited following Wnt ligand presentation. The precise mechanism underlying β‐catenin destruction complex inhibition is not clear, nor is the exact role of APC in the complex. APC is primarily considered a core component of the destruction complex but has been shown to have other roles involving β‐catenin nuclear import/export and cytoskeletal functions. Here, we use Wnt3a beads to study the response of endogenous Wnt components to a local Wnt cue. Using three CRC cell lines, each with a different Wnt pathway status, we demonstrate that localized Wnt redistributes pathway components toward the Wnt source in the presence of full‐length, but not truncated APC. Further, use of the Wnt3a‐beads to perform protein pull‐down demonstrates that APC and β‐catenin both associate with the Wnt‐beads. APC depletion in nontransformed human colon epithelial cells diminishes this Wnt‐induced redistribution. Our results suggest revision of the current model as follows. In response to Wnt, the β‐catenin destruction complex: 1) maintains composition and binding to β‐catenin, 2) translocates to the plasma membrane, and 3) requires full‐length APC for this membrane trafficking. Currently, work is being performed to uncover mechanistic insights into the role of APC in destruction complex reorientation to a Wnt3a signal. Support or Funding Information This study was supported by the National Science Foundation [grant number IOS‐1456538] and by the National Institutes of Health [P30CA168524].