APC mutations disrupt β-catenin destruction complex condensates organized by Axin phase separation

• Published in: Cellular and molecular life sciences : CMLS 2024-12, Vol.81 (1), p.57-57, Article 57
• Main Authors: Zhang, Dan, Ni, Qi-Qi, Wang, Shu-Yang, He, Wen-Feng, Hong, Ze-Xuan, Liu, Hui-Ye, Chen, Xiao-Hong, Chen, Li-Jie, Han, Fang-Yi, Zhang, Ling-Jie, Li, Xiao-ming, Ding, Yan-qing, Jiao, Hong-li, Ye, Ya-ping
• Format: Article
• Language: English
• Subjects: Adenomatous Polyposis Coli Protein - genetics; Adenomatous Polyposis Coli Protein - metabolism; APC gene; Axin Protein - genetics; Axin Protein - metabolism; Axin Signaling Complex - genetics; beta Catenin - genetics; beta Catenin - metabolism; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell fate; Colorectal cancer; Colorectal carcinoma; Condensates; Cytoplasm; Destruction; Humans; Life Sciences; Liquid phases; Molecular modelling; Mutation; Mutation - genetics; Original; Original Article; Phase Separation; Phosphorylation; Signal transduction; Translocation; Wnt protein; Wnt Signaling Pathway - genetics; β-Catenin
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-023-05068-0

The Wnt/β-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid–liquid-phase separation (LLPS) of Axin organized the β-catenin destruction complex condensates in a normal cellular state. Mutations inactivating the APC gene are found in approximately 80% of all human colorectal cancer (CRC). However, the molecular mechanism of the formation of β-catenin destruction complex condensates organized by Axin phase separation and how APC mutations impact the condensates are still unclear. Here, we report that the β-catenin destruction complex, which is constructed by Axin, was assembled condensates via a phase separation process in CRC cells. The key role of wild-type APC is to stabilize destruction complex condensates. Surprisingly, truncated APC did not affect the formation of condensates, and GSK 3β and CK1α were unsuccessfully recruited, preventing β-catenin phosphorylation and resulting in accumulation in the cytoplasm of CRCs. Besides, we propose that the phase separation ability of Axin participates in the nucleus translocation of β-catenin and be incorporated and concentrated into transcriptional condensates, affecting the transcriptional activity of Wnt signaling pathway.