Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells

Sayaka Saitoh, Takeshi Maruyama, Yuta Yako, Mihoko Kajita, Yoichiro Fujioka, Yusuke Ohba, Nobuhiro Kasai, Natsu Sugama, Shunsuke Kon, Susumu Ishikawa, Takashi Hayashi, Tomohiro Yamazaki, Masazumi Tada, Yasuyuki Fujita

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16 Citations (Scopus)

Abstract

Newly emerging transformed cells are often eliminated from epithelial tissues. Recent studies have revealed that this cancer-preventive process involves the interaction with the surrounding normal epithelial cells; however, the molecular mechanisms underlying this phenomenon remain largely unknown. In this study, using mammalian cell culture and zebrafish embryo systems, we have elucidated the functional involvement of endocytosis in the elimination of RasV12- transformed cells. First, we show that Rab5, a crucial regulator of endocytosis, is accumulated in RasV12-transformed cells that are surrounded by normal epithelial cells, which is accompanied by upregulation of clathrin-dependent endocytosis. Addition of chlorpromazine or coexpression of a dominant-negative mutant of Rab5 suppresses apical extrusion of RasV12 cells from the epithelium. We also show in zebrafish embryos that Rab5 plays an important role in the elimination of transformed cells from the enveloping layer epithelium. In addition, Rab5-mediated endocytosis of E-cadherin is enhanced at the boundary between normal and RasV12 cells. Rab5 functions upstream of epithelial protein lost in neoplasm (EPLIN), which plays a positive role in apical extrusion of RasV12 cells by regulating protein kinase A. Furthermore, we have revealed that epithelial defense against cancer (EDAC) from normal epithelial cells substantially impacts on Rab5 accumulation in the neighboring transformed cells. This report demonstrates that Rab5-mediated endocytosis is a crucial regulator for the competitive interaction between normal and transformed epithelial cells in mammals.

Original languageEnglish
Pages (from-to)E2327-E2336
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number12
DOIs
Publication statusPublished - 2017 Mar 21

Keywords

  • Apical extrusion
  • Cell competition
  • Endocytosis
  • Rab5
  • RasV12

ASJC Scopus subject areas

  • General

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    Saitoh, S., Maruyama, T., Yako, Y., Kajita, M., Fujioka, Y., Ohba, Y., Kasai, N., Sugama, N., Kon, S., Ishikawa, S., Hayashi, T., Yamazaki, T., Tada, M., & Fujita, Y. (2017). Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells. Proceedings of the National Academy of Sciences of the United States of America, 114(12), E2327-E2336. https://doi.org/10.1073/pnas.1602349114