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Loss of Rab5 drives non-autonomous cell proliferation through TNF and Ras signaling in Drosophila
Authors:Kyoko Takino  Shizue Ohsawa  Tatsushi Igaki
Affiliation:1. Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoecho-cho, Sakyo-ku, Kyoto 606-8501, Japan;2. Division of Genetics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan;3. PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan
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.
Keywords:Tissue growth regulation   Cell&ndash  cell interaction   Tumorigenesis   Rab5   Drosophila
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