Multivalent tumor suppressor adenomatous polyposis coli promotes Axin biomolecular condensate formation and efficient \u03b2-catenin degradation

Tie-Mei Li,Katrin F Chua,Jing Ren,Dylan Husmann,Or Gozani,John P Coan

doi:10.1038/s41598-020-74080-2

Abstract

The tumor suppressor adenomatous polyposis coli (APC) is frequently mutated in colorectal cancers. APC and Axin are core components of a destruction complex that scaffolds GSK3β and CK1 to earmark β-catenin for proteosomal degradation. Disruption of APC results in pathologic stabilization of β-catenin and oncogenesis. However, the molecular mechanism by which APC promotes β-catenin degradation is unclear. Here, we find that the intrinsically disordered region (IDR) of APC, which contains multiple β-catenin and Axin interacting sites, undergoes liquid–liquid phase separation (LLPS) in vitro. Expression of the APC IDR in colorectal cells promotes Axin puncta formation and β-catenin degradation. Our results support the model that multivalent interactions between APC and Axin drives the β-catenin destruction complex to form biomolecular condensates in cells, which concentrate key components to achieve high efficient degradation of β-catenin.

Highlights

The tumor suppressor adenomatous polyposis coli (APC) is frequently mutated in colorectal cancers
To determine the downstream consequences of APC intrinsically disordered region (IDR) and Axin[1] co-expression, we examined the level of endogenous β-catenin protein. mCherry-Axin[1] expression caused a moderate reduction of β-catenin protein level compared with nontransfected cells (Fig. 3A)
We showed that multivalent APC IDRs are able to phase separate in vitro (Figs. 1, 2)

Summary

Introduction

The tumor suppressor adenomatous polyposis coli (APC) is frequently mutated in colorectal cancers. Our results support the model that multivalent interactions between APC and Axin drives the β-catenin destruction complex to form biomolecular condensates in cells, which concentrate key components to achieve high efficient degradation of β-catenin. Proximity of β-catenin to the two kinases leads to β-catenin phosphorylation, which in turn facilitates its ubiquitination and proteosomal degradation Both APC and Axin are key for the function of the β-catenin destruction c omplex[3]. In the colorectal cancer cell line SW480, APC IDR promotes Axin puncta formation and efficient β-catenin degradation. Our data support a model in which APC IDR and its multivalent interactions with Axin promote biocondensates formation, acting to recruit and concentrate key components within a physically separated compartment and thereby increase the efficiency of β-catenin degradation

Methods

Results

Conclusion