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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月22日

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  • Dan Xiang,
  • Wenfeng Wu,
  • Ruona Shi,
  • Xiaoxiao Tang,
  • Xiaofei Zhang

摘要

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.