2. Academic Validation
  3. TRAF2 mediates Wnt-induced β-catenin nuclear translocation by associating with the nuclear pore complex

TRAF2 mediates Wnt-induced β-catenin nuclear translocation by associating with the nuclear pore complex

  • Life Sci. 2025 Sep 15:377:123722. doi: 10.1016/j.lfs.2025.123722.
Min Yang 1,  Ying Xuan 1,  Piliang Hao 2,  Yushu Li 1,  Chengqian Zhang 2,  Weiwei Zhao 1,  Yiyuan Zhang 1,  Xue Zhang 1,  Xianglian Zhou 1,  Hongyan Zhu 1,  Huihui Li 1,  Yan Yang 1,  Jiaqi Wang 1,  Rong Yan 3,  Yi Qu 4,  Xisong Ke 5
Affiliations

Affiliations

  • 1 Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China; State Key Laboratory of Integration and Innovation of Classical Formula and Modern Chinese Medicine, Shanghai, PR China.
  • 2 School of Life Science and Technology, Shanghai Tech University, Shanghai, PR China.
  • 3 Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China; State Key Laboratory of Integration and Innovation of Classical Formula and Modern Chinese Medicine, Shanghai, PR China. Electronic address: yanrong@shutcm.edu.cn.
  • 4 Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China; State Key Laboratory of Integration and Innovation of Classical Formula and Modern Chinese Medicine, Shanghai, PR China. Electronic address: yiqu@shutcm.edu.cn.
  • 5 Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China; State Key Laboratory of Integration and Innovation of Classical Formula and Modern Chinese Medicine, Shanghai, PR China. Electronic address: xisongke@shutcm.edu.cn.
PMID: 40393561 DOI: 10.1016/j.lfs.2025.123722
Abstract

Aims: Colorectal Cancer (CRC), driven by Wnt/β-catenin hyperactivation, relies on nuclear import of β-catenin, but the underlying mechanism is not fully clarified. Given that tumor necrosis factor receptor-associated factor 2 (TRAF2) is a positive regulator of Wnt signaling by directly interacting with β-catenin, we aim to demonstrate the role of TRAF2 in Wnt-induced β-catenin nuclear translocation.

Materials and methods: Wild-type and TRAF2 knockout cells (generated via CRISPR-Cas9) were utilized to validate the role of TRAF2 in β-catenin nuclear translocation through immunofluorescence and nucleoplasm separation assay. Proteomic profiling of TRAF2 condensates and interactomes was performed to identify proteins linked to nucleocytoplasmic transport. The interactions among TRAF2, β-catenin, nucleoporins (Nups) and B-cell lymphoma 9 (BCL9), as well as the inhibitory effects of small molecule liquidambaric acid (LDA) on these interactions were confirmed using proximity ligation assay (PLA), fluorescence resonance energy transfer (FRET), and co-immunoprecipitation (Co-IP) in cellular models and small intestine of mice.

Key findings: TRAF2 is required for Wnt-induced β-catenin nuclear translocation. TRAF2 interacts with numerous Nups within the nuclear pore complex (NPC), and is upregulated upon Wnt stimulation. In the small intestine of mice, TRAF2/Nups interaction is mainly detected in the crypts-regions known to harbor colorectal Cancer Stem Cells, as well as in APCmin/+ intestinal organoids. Of note, TRAF2 is indispensable for β-catenin interaction with Nups and the known chaperone BCL9. Finally, LDA blocks TRAF2/Nups interaction, inhibiting β-catenin nuclear translocation.

Significance: This study unveils TRAF2-mediated nucleocytoplasmic transport as a druggable mechanism, advancing targeted therapies against Wnt-driven colorectal cancers.

Keywords

Beta-catenin (β-catenin); Colorectal cancer (CRC); Nuclear pore complex; Nuclear translocation; Nucleoporins; Proteomics; TRAF2.

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