title: Loss of Rab5 drives non-autonomous cell proliferation through TNF and Ras signaling in Drosophila.
abstract: Deregulation of the endocytic machinery has been implicated in human cancers. However, the mechanism by which endocytic defects drive cancer development remains to be clarified. Here, we find through a genetic screen in Drosophila that loss of Rab5, a protein required for early endocytic trafficking, drives non-autonomous cell proliferation in imaginal epithelium. Our genetic data indicate that dysfunction of Rab5 leads to cell-autonomous accumulation of Eiger (a TNF homolog) and EGF receptor (EGFR), which causes activation of downstream JNK and Ras signaling, respectively. JNK signaling and its downstream component Cdc42 cooperate with Ras signaling to induce upregulation of a secreted growth factor Upd (an IL-6 homolog) through inactivation of the Hippo pathway. Such non-autonomous tissue growth triggered by Rab5 defect could contribute to epithelial homeostasis as well as cancer development within heterogeneous tumor microenvironment.
authors.affiliation: Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoecho-cho, Sakyo-ku, Kyoto 606-8501, Japan; Division of Genetics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takino
authors.affiliation: Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoecho-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Shizue
authors.initials: S
authors.lastname: Ohsawa
authors.affiliation: Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoecho-cho, Sakyo-ku, Kyoto 606-8501, Japan; PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan. Electronic address: igaki@lif.kyoto-u.ac.jp.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Igaki
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005123:Eye / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D060227:Imaginal Discs / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D029721:Drosophila Proteins; D066246:ErbB Receptors; D019204:GTP-Binding Proteins; D049452:Green Fluorescent Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D020696:rab5 GTP-Binding Proteins; D018631:ras Proteins; C090145:Cdc42 protein, Drosophila; C464573:egr protein, Drosophila; C115570:upd1 protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases; C586289:Rab5 protein, Drosophila
keywords: Cell–cell interaction; Drosophila; Rab5; Tissue growth regulation; Tumorigenesis