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

Cell Death & Differentiation (2026)Cite this article

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Abstract

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.

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Fig. 1: ARHGAP36 is associated with entotic cell-in-cell formation.
Fig. 2: ARHGAP36 promotes entotic cell-in-cell formation.
Fig. 3: Tumor suppressive effects of ARHGAP36.
Fig. 4: ARHGAP36 promotes the expression of adhesion molecules and mediates cell adhesion.
Fig. 5: ARHGAP36 stabilizes the P-cadherin complex by interacting with β-catenin.
Fig. 6: The Arg-rich domain stables P-cadherin complex.
Fig. 7: ARHGAP36 mislocation blocks CIC formation.
Fig. 8: ARHGAP36 promotes actomyosin contraction.
Fig. 9: PKA involvement in ARHGAP36-regulated CIC formation.
Fig. 10: ARHGAP36 parallelly regulates actomyosin and adherens junction.

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Acknowledgements

This research was financially supported by the National Key Research and Development Program of China (Nos. 2023YFA0914900 and 2022YFA0912400), the National Natural Science Foundation of China (NSFC) Grants (Nos. 32100608, 82273184, 82373069 and 82002918), China Postdoctoral Science Foundation (No. 88014Y0119), the CAMS Innovation Fund for Medical Sciences (2021-I2M-5-008), Hainan Provincial Association for Science and Technology Young Talent Innovation Program (QCXM202017), and Hainan Provincial Natural Science Foundation High-level Talent Project (820RC639).

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Author notes

  1. These authors contributed equally: Banzhan Ruan, Chenxi Wang, Xinyue Gao.

Authors and Affiliations

  1. Academy of Military Medical Sciences; Research Unit of Cell Death Mechanism, Chinese Academy of Medical Science, 2021RU008, Beijing, China

    Banzhan Ruan, Chenxi Wang, Xinyue Gao, Zhengrong Zhang, Zubiao Niu, Jianqing Liang, Bo Zhang, Linjing Liu, You Zheng, Xin Zhang, Zhuoran Sun & Qiang Sun

  2. Department of Biology, Hainan Medical University, Haikou, Hainan, China

    Banzhan Ruan

  3. Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China

    Banzhan Ruan, Zhengrong Zhang, Bo Zhang & Hongyan Huang

  4. Medical School of Nanjing University, Nanjing University, Nanjing, China

    Linjing Liu

  5. Department of Pediatric Hematology and Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China

    Xin Zhang

  6. Laboratory of General Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Meifang He

  7. Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy

    Gerry Melino

  8. School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515 & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China

    Xiaoning Wang

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Contributions

QS, HH, and XW conceived and supervised the project. BR and CW performed most experiments with the help from ZZ, XG, ZN, JL, BZ, LL, YZ, XZ, ZS, and MH in agents, data acquisition, analysis and interpretation, and statistical analysis. XG and LL primarily accomplished revision. QS, HH, XW, and GM prepared the figures, wrote the manuscript with inputs from other authors. All authors read and approved the final paper.

Corresponding authors

Correspondence to Xiaoning Wang, Hongyan Huang or Qiang Sun.

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All experiments involving animals were conducted in strict accordance with the guidelines set by the Chinese Regulations of Laboratory Animals and Laboratory Animal-Requirements of Environment and Housing Facilities, approved by the Experimental Animal Committee of Laboratory Animal Center, AMMS (Approval number: ICAUC-DWZX-2021-036).

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Ruan, B., Wang, C., Gao, X. et al. ARHGAP36 imposes a bifurcate activation of adherens junction and actomyosin to promote entosis. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01668-y

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