2. Academic Validation
  3. UBE2O-mediated ubiquitylation directs cytoplasmic CTNNA1 to promote cell-to-ECM adhesions

UBE2O-mediated ubiquitylation directs cytoplasmic CTNNA1 to promote cell-to-ECM adhesions

  • EMBO Rep. 2025 Sep 22. doi: 10.1038/s44319-025-00585-4.
Dan Xiang 1 2 3,  Wenfeng Wu 4,  Ruona Shi 5,  Xiaoxiao Tang 1 2 3,  Xiaofei Zhang 6 7 8
Affiliations

Affiliations

  • 1 Laboratory of Proteomics and Ubiquitin Signaling, Center for Cell Lineage Altas, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China.
  • 3 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, the Fifth Affiliated Hospital of Guangzhou Medical University, 510799, Guangzhou, Guangdong, China.
  • 5 Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, 15 Science Park West Avenue, Hong Kong Science Park, Hong Kong SAR, China.
  • 6 Laboratory of Proteomics and Ubiquitin Signaling, Center for Cell Lineage Altas, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China. zhang_xiaofei@gibh.ac.cn.
  • 7 Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China. zhang_xiaofei@gibh.ac.cn.
  • 8 University of Chinese Academy of Sciences, Beijing, 100049, China. zhang_xiaofei@gibh.ac.cn.
PMID: 40983751 DOI: 10.1038/s44319-025-00585-4
Abstract

CTNNA1, a multifunctional protein that localizes at both the plasma membrane and the cytosol, plays crucial roles in actin dynamics regulation, cell-to-cell and cell-to-the extracellular matrix (ECM) adhesions and tumor suppression. Despite its diverse functions, the regulatory mechanisms by which cells coordinate CTNNA1's roles remain poorly understood. In this study, we identified UBE2O, a unique hybrid E2/E3 enzyme, as a key regulator that selectively interacts with and ubiquitylates cytosolic CTNNA1 in a phosphorylation-independent manner. Through comprehensive mass spectrometry-based interactome analysis of ubiquitylated CTNNA1, we reveal that the ubiquitylation of CTNNA1 diminishes its interaction with β-catenin while allowing its interaction with vinculin. This switch of molecular interactions promotes focal adhesions maturation, facilitates cell extension and matrix adhesion during the initial phases of cell spreading. Importantly, our findings demonstrate that ubiquitylation serves as a molecular switch that directs the regulatory roles of CTNNA1 to cell-to-ECM adhesions. This study advances our understanding of how ubiquitylation fine-tunes protein function in cell adhesion dynamics.

Keywords

CTNNA1; Cell Adhesions; Proteomics; UBE2O; Ubiquitylation.

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