title: Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells.
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 up-regulation 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.
authors.affiliation: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.|Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Saitoh
authors.affiliation: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.|Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Maruyama
authors.affiliation: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.|Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Yako
authors.affiliation: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.|Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Kajita
authors.affiliation: Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Fujioka
authors.affiliation: Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
authors.affiliation: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.|Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kasai
authors.affiliation: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Natsu
authors.initials: N
authors.lastname: Sugama
authors.affiliation: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.|Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kon
authors.affiliation: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.|Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishikawa
authors.affiliation: Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0815, Japan.|Biomedical Technology Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima 771-0192, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Division of RNA Biofunction, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Masazumi
authors.initials: M
authors.lastname: Tada
authors.affiliation: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; yasu@igm.hokudai.ac.jp.|Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fujita
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D004705:Endocytosis; D004848:Epithelium / Q000196:embryology / Q000378:metabolism; D015398:Signal Transduction; D014170:Transformation, Genetic; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D029961:Zebrafish Proteins; D020696:rab5 GTP-Binding Proteins
keywords: Rab5; RasV12; apical extrusion; cell competition; endocytosis