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.