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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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