scholarly journals Multivalent tumor suppressor adenomatous polyposis coli promotes Axin biomolecular condensate formation and efficient β-catenin degradation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tie-Mei Li ◽  
Jing Ren ◽  
Dylan Husmann ◽  
John P. Coan ◽  
Or Gozani ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Adenomatous Polyposis Coli ◽  
Adenomatous Polyposis ◽  
Polyposis Coli ◽  
Intrinsically Disordered ◽  
High Efficient ◽  
Condensate Formation ◽  
Core Components ◽  
Liquid Liquid Phase Separation

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.

scholarly journals Phase separation of Axin organizes the β-catenin destruction complex

2021 ◽  
Vol 220 (4) ◽  
Author(s):  
Junxiu Nong ◽  
Kexin Kang ◽  
Qiaoni Shi ◽  
Xuechen Zhu ◽  
Qinghua Tao ◽  
...  
Keyword(s):  
Phase Separation ◽  
Glycogen Synthase ◽  
Adenomatous Polyposis ◽  
Compelling Evidence ◽  
Glycogen Synthase Kinase 3Β ◽  
Polyposis Coli ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Region ◽  
Liquid Liquid Phase Separation

In Wnt/β-catenin signaling, the β-catenin protein level is deliberately controlled by the assembly of the multiprotein β-catenin destruction complex composed of Axin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), and others. Here we provide compelling evidence that formation of the destruction complex is driven by protein liquid–liquid phase separation (LLPS) of Axin. An intrinsically disordered region in Axin plays an important role in driving its LLPS. Phase-separated Axin provides a scaffold for recruiting GSK3β, CK1α, and β-catenin. APC also undergoes LLPS in vitro and enhances the size and dynamics of Axin phase droplets. The LLPS-driven assembly of the destruction complex facilitates β-catenin phosphorylation by GSK3β and is critical for the regulation of β-catenin protein stability and thus Wnt/β-catenin signaling.

scholarly journals Interaction between Tumor Suppressor Adenomatous Polyposis Coli and Topoisomerase IIα: Implication for the G2/M Transition

2008 ◽  
Vol 19 (10) ◽  
pp. 4076-4085 ◽  
Author(s):  
Yang Wang ◽  
Yoshiaki Azuma ◽  
David Moore ◽  
Neil Osheroff ◽  
Kristi L. Neufeld
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Adenomatous Polyposis Coli ◽  
Fluorescent Protein ◽  
Adenomatous Polyposis ◽  
Polyposis Coli ◽  
Topoisomerase Iiα ◽  
Nuclear Localization Signals

The tumor suppressor adenomatous polyposis coli (APC) is implicated in regulating multiple stages of the cell cycle. APC participation in G1/S is attributed to its recognized role in Wnt signaling. APC function in the G2/M transition is less well established. To identify novel protein partners of APC that regulate the G2/M transition, APC was immunoprecipitated from colon cell lysates and associated proteins were analyzed by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF). Topoisomerase IIα (topo IIα) was identified as a potential binding partner of APC. Topo IIα is a critical regulator of G2/M transition. Evidence supporting an interaction between endogenous APC and topo IIα was obtained by coimmunoprecipitation, colocalization, and Förster resonance energy transfer (FRET). The 15-amino acid repeat region of APC (M2-APC) interacted with topo IIα when expressed as a green fluorescent protein (GFP)-fusion protein in vivo. Although lacking defined nuclear localization signals (NLS) M2-APC predominantly localized to the nucleus. Furthermore, cells expressing M2-APC displayed condensed or fragmented nuclei, and they were arrested in the G2 phase of the cell cycle. Although M2-APC contains a β-catenin binding domain, biochemical studies failed to implicate β-catenin in the observed phenotype. Finally, purified recombinant M2-APC enhanced topo IIα activity in vitro. Together, these data support a novel role for APC in the G2/M transition, potentially through association with topo IIα.

scholarly journals Adenomatous Polyposis Coli Tumor Suppressor Protein Has Signaling Activity in Xenopus laevis Embryos Resulting in the Induction of an Ectopic Dorsoanterior Axis

1997 ◽  
Vol 136 (2) ◽  
pp. 411-420 ◽  
Author(s):  
Kris Vleminckx ◽  
Ellen Wong ◽  
Kathy Guger ◽  
Bonnee Rubinfeld ◽  
Paul Polakis ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumor Suppressor ◽  
Adenomatous Polyposis Coli ◽  
Protein A ◽  
Homeobox Gene ◽  
Xenopus Embryo ◽  
Adenomatous Polyposis ◽  
Polyposis Coli ◽  
Human Colon Cancer ◽  
Signaling Activity

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene are linked to both familial and sporadic human colon cancer. So far, a clear biological function for the APC gene product has not been determined. We assayed the activity of APC in the early Xenopus embryo, which has been established as a good model for the analysis of the signaling activity of the APC-associated protein β-catenin. When expressed in the future ventral side of a four-cell embryo, full-length APC induced a secondary dorsoanterior axis and the induction of the homeobox gene Siamois. This is similar to the phenotype previously observed for ectopic β-catenin expression. In fact, axis induction by APC required the availability of cytosolic β-catenin. These results indicate that APC has signaling activity in the early Xenopus embryo. Signaling activity resides in the central domain of the protein, a part of the molecule that is missing in most of the truncating APC mutations in colon cancer. Signaling by APC in Xenopus embryos is not accompanied by detectable changes in expression levels of β-catenin, indicating that it has direct positive signaling activity in addition to its role in β-catenin turnover. From these results we propose a model in which APC acts as part of the Wnt/β-catenin signaling pathway, either upstream of, or in conjunction with, β-catenin.

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