1. APC mutations disrupt β-catenin destruction complex condensates organized by Axin phase separation.
- Author
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Zhang D, Ni QQ, Wang SY, He WF, Hong ZX, Liu HY, Chen XH, Chen LJ, Han FY, Zhang LJ, Li XM, Ding YQ, Jiao HL, and Ye YP
- Subjects
- Humans, Axin Protein genetics, Axin Protein metabolism, Phase Separation, Mutation genetics, Wnt Signaling Pathway genetics, Adenomatous Polyposis Coli Protein genetics, Adenomatous Polyposis Coli Protein metabolism, Axin Signaling Complex genetics, beta Catenin genetics, beta Catenin metabolism
- Abstract
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., (© 2024. The Author(s).)
- Published
- 2024
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