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Dev Biol. 2014 Nov 1;395(1):19-28. doi: 10.1016/j.ydbio.2014.09.003. Epub 2014 Sep 16.

Loss of Rab5 drives non-autonomous cell proliferation through TNF and Ras signaling in Drosophila.

Author information

1
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.
2
Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoecho-cho, Sakyo-ku, Kyoto 606-8501, Japan.
3
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.

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:

Cell–cell interaction; Drosophila; Rab5; Tissue growth regulation; Tumorigenesis

PMID:
25224221
DOI:
10.1016/j.ydbio.2014.09.003
[Indexed for MEDLINE]
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