Abstract
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 InformationThis study was supported by the National Science Foundation [grant number IOS‐1456538] and by the National Institutes of Health [P30CA168524].
Highlights
Wnt/β-catenin signaling is essential for intestinal homeostasis and is aberrantly activated in most colorectal cancers (CRC) through mutation of the tumor suppressor Adenomatous Polyposis Coli (APC)
Since APC is mutated in >80% of colorectal cancers and is a major scaffolding protein for the β-catenin destruction complex, we first asked whether APC redistributes toward a localized Wnt3a signal in a panel of human CRC cell lines
The phenotypic consequences of truncated APC have been previously postulated to act in a “just-right” signaling model, in which truncated APC retains partial β-catenin regulatory function to allow a specific level of Wnt activation[21]
Summary
Wnt/β-catenin signaling is essential for intestinal homeostasis and is aberrantly activated in most colorectal cancers (CRC) through mutation of the tumor suppressor Adenomatous Polyposis Coli (APC). The endogenous β-catenin destruction complex reoriented toward the local Wnt cue in CRC cells with full-length APC, but not if APC was truncated or depleted. Non-transformed human colon epithelial cells displayed similar Wnt-induced destruction complex localization which appeared to be dependent on APC and less so on Axin. Wnt ligands are required for intestinal stem cell (ISC) self-renewal and crypt homeostasis[15,16,17]. Prior research has mostly relied on overexpression of specific Wnt pathway components or cells treated with soluble Wnt in the media, limiting the ability to elucidate endogenous β-catenin destruction complex dynamics in response to a local Wnt signal (reviewed in[3])
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