期刊
DEVELOPMENTAL BIOLOGY
卷 403, 期 2, 页码 162-171出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ydbio.2015.05.001
关键词
JNK; Ras; Hippo signaling; Tumor progression
资金
- Japanese Ministry of Education, Science, Sports, Culture and Technology (MEXT)
- MEXT
- Platform for Dynamic Approaches to Living System from MEXT
- Japan Society for the Promotion of Science (JSPS)
- Uehara Memorial Foundation
- Tomizawa & Keiko Fund of Molecular Biology Society of Japan for Young Scientist
- Takeda Science Foundation
- Suzuken Memorial Foundation
- Inamori Foundation
- Naito Foundation
- PRESTO
- Japan Science and Technology Agency (JST)
- International Human Frontier Science Program
- JSPS Postdoctoral Fellowship
- Grants-in-Aid for Scientific Research [15H05856, 26670141] Funding Source: KAKEN
The c-Jun N-terminal kinase (JNK) pathway is a dual-functional oncogenic signaling that exerts both anti- and pro-tumor activities. However, the mechanism by which JNK switches its oncogenic roles depending on different cellular contexts has been elusive. Here, using the Drosophila genetics, we show that hyperactive Ras acts as a signaling switch that converts JNK's role from anti- to pro-tumor signaling through the regulation of Hippo signaling activity. In the normal epithelium, JNK signaling antagonizes the Hippo pathway effector Yorkie (Yki) through elevation of Warts activity, thereby suppressing tissue growth. In contrast, in the presence of hyperactive Ras, JNK signaling enhances Yki activation by accumulating F-actin through the activity of the LIM domain protein Ajuba, thereby promoting tissue growth. We also find that the epidermal growth factor receptor (EGFR) signaling uses this Ras-mediated conversion of JNK signaling to promote tissue growth. Our observations suggest that Ras-mediated switch of the JNK pathway from anti- to pro-tumor signaling could play crucial roles in tumorigenesis as well as in normal development. (C) 2015 Elsevier Inc. All rights reserved.
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