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<p>Entosis is a non-apoptotic cell death process implicated in various important biological processes, such as tumorigenesis. Entotic death is preceded with the formation of cell-in-cell structures that are well known to be controlled by two spatially separated core elements: adherens junction and actomyosin. However, the molecular mechanism underlying their coordination remains a longstanding open question. In this study, by profiling isogenic breast cancer cells, ARHGAP36 was identified as a potent inducer of entotic cell-in-cell formation, consistent with multiple lines of tumor-suppressive evidence both in vitro and in vivo. This effect is attributed to the concomitant promotion of P-cadherin-mediated cell-cell adhesion and RhoA-regulated actomyosin contraction. Mechanistically, ARHGAP36, through the arginine-rich domain at the N-terminal, binds to β-catenin to stabilize P-cadherin expression in a way accompanying with, and mutually exclusive from, its interaction with PKAc to activate RhoA signaling. Thus, this study unveiled a heretofore unrecognized coordination mechanism for entosis, where ARHGAP36 engages both adherens junction and actomyosin to drive cell-in-cell formation, providing a promising cancer therapeutic target.</p>

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ARHGAP36 imposes a bifurcate activation of adherens junction and actomyosin to promote entosis

  • 期刊论文

  • 发表日期：

    2026年2月5日

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  • Banzhan Ruan,
  • Chenxi Wang,
  • Xinyue Gao,
  • Zhengrong Zhang,
  • Zubiao Niu,
  • Jianqing Liang,
  • Bo Zhang,
  • Linjing Liu,
  • You Zheng,
  • Xin Zhang,
  • Zhuoran Sun,
  • Meifang He,
  • Gerry Melino,
  • Xiaoning Wang,
  • Hongyan Huang,
  • Qiang Sun

摘要

Entosis is a non-apoptotic cell death process implicated in various important biological processes, such as tumorigenesis. Entotic death is preceded with the formation of cell-in-cell structures that are well known to be controlled by two spatially separated core elements: adherens junction and actomyosin. However, the molecular mechanism underlying their coordination remains a longstanding open question. In this study, by profiling isogenic breast cancer cells, ARHGAP36 was identified as a potent inducer of entotic cell-in-cell formation, consistent with multiple lines of tumor-suppressive evidence both in vitro and in vivo. This effect is attributed to the concomitant promotion of P-cadherin-mediated cell-cell adhesion and RhoA-regulated actomyosin contraction. Mechanistically, ARHGAP36, through the arginine-rich domain at the N-terminal, binds to β-catenin to stabilize P-cadherin expression in a way accompanying with, and mutually exclusive from, its interaction with PKAc to activate RhoA signaling. Thus, this study unveiled a heretofore unrecognized coordination mechanism for entosis, where ARHGAP36 engages both adherens junction and actomyosin to drive cell-in-cell formation, providing a promising cancer therapeutic target.