Reference - Detail
|Author||Takino K, Ohsawa S, Igaki T.|
|Title||Loss of Rab5 drives non-autonomous cell proliferation through TNF and Ras signaling in Drosophila.|
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.
|MeSH||Animals Animals, Genetically Modified Cell Proliferation* Drosophila Proteins / genetics Drosophila Proteins / metabolism* Drosophila melanogaster / genetics Drosophila melanogaster / metabolism ErbB Receptors / genetics ErbB Receptors / metabolism Eye / metabolism GTP-Binding Proteins / genetics GTP-Binding Proteins / metabolism Green Fluorescent Proteins / genetics Green Fluorescent Proteins / metabolism Humans Imaginal Discs / metabolism Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism JNK Mitogen-Activated Protein Kinases / genetics JNK Mitogen-Activated Protein Kinases / metabolism Membrane Proteins / genetics Membrane Proteins / metabolism Microscopy, Confocal Models, Biological Models, Genetic Mutation Protein-Serine-Threonine Kinases / genetics Protein-Serine-Threonine Kinases / metabolism RNA Interference Signal Transduction* Transcription Factors / genetics Transcription Factors / metabolism Tumor Necrosis Factor-alpha / genetics Tumor Necrosis Factor-alpha / metabolism* rab5 GTP-Binding Proteins / genetics rab5 GTP-Binding Proteins / metabolism* ras Proteins / genetics ras Proteins / metabolism*|
|WOS Category||DEVELOPMENTAL BIOLOGY|