期刊
NATURE
卷 542, 期 7640, 页码 246-250出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature21033
关键词
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资金
- MEXT/JSPS KAKENHI [26114002, 25112710, 15H05862, 23127508]
- Nakajima Foundation
- Inoue Science Research Award
- Naito Foundation
- Takeda Science Foundation
- JST
- Platform for Dynamic Approaches to Living System from AMED
- Grants-in-Aid for Scientific Research [15K21726, 26711013, 25112710, 15H05862, 26114002, 23127508] Funding Source: KAKEN
Normal epithelial cells often exert anti-tumour effects against nearby oncogenic cells. In the Drosophila imaginal epithelium, clones of oncogenic cells with loss-of-function mutations in the apico-basal polarity genes scribble or discs large are actively eliminated by cell competition when surrounded by wild-type cells'. Although c-Jun N-terminal kinase (JNK) signalling plays a crucial role in this cell elimination(1-5), the initial event, which occurs at the interface between normal cells and polarity-deficient cells, has not previously been identified. Here, through a genetic screen in Drosophila, we identify the ligand Sas and the receptor-type tyrosine phosphatase PTP10D as the cell-surface ligand-receptor system that drives tumour-suppressive cell competition. At the interface between the wild-type 'winner' and the polarity-deficient 'loser' clones, winner cells relocalize Sas to the lateral cell surface, whereas loser cells relocalize PTP10D there. This leads to the trans activation of Sas-PTP10D signalling in loser cells, which restrains EGFR signalling and thereby enables elevated JNK signalling in loser cells, triggering cell elimination. In the absence of Sas-PTP10D, elevated EGFR signalling in loser cells switches the role of JNK from pro-apoptotic to pro-proliferative by inactivating the Hippo pathway, thereby driving the overgrowth of polarity-deficient cells. These findings uncover the mechanism by which normal epithelial cells recognize oncogenic polarity-deficient neighbours to drive cell competition.
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