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Phase separation of EML4-ALK in firing downstream signaling and promoting lung tumorigenesis | |
Qin, Zhen1,2; Sun, Honghua1,2; Yue, Meiting1,2; Pan, Xinwen1,3; Chen, Liang4; Feng, Xinhua5; Yan, Xiumin1,2; Zhu, Xueliang1,2,3,6; Ji, Hongbin1,2,3 | |
2021-05-11 | |
发表期刊 | CELL DISCOVERY |
EISSN | 2056-5968 |
卷号 | 7期号:1 |
DOI | 10.1038/s41421-021-00270-5 |
摘要 | EML4-ALK fusion, observed in about 3%-7% of human lung adenocarcinoma, is one of the most important oncogenic drivers in initiating lung tumorigenesis. However, it still remains largely unknown about how EML4-ALK fusion exactly fires downstream signaling and drives lung cancer formation. We here find that EML4-ALK variant 1 (exon 1-13 of EML4 fused to exon 20-29 of ALK) forms condensates via phase separation in the cytoplasm of various human cancer cell lines. Using two genetically engineered mouse models (GEMMs), we find that EML4-ALK variant 1 can drive lung tumorigenesis and these murine tumors, as well as primary tumor-derived organoids, clearly show the condensates of EML4-ALK protein, further supporting the findings from in vitro study. Mutation of multiple aromatic residues in EML4 region significantly impairs the phase separation of EML4-ALK and dampens the activation of the downstream signaling pathways, especially the STAT3 phosphorylation. Importantly, it also significantly decreases cancer malignant transformation and tumor formation. These data together highlight an important role of phase separation in orchestrating EML4-ALK signaling and promoting tumorigenesis, which might provide new clues for the development of clinical therapeutic strategies in treating lung cancer patients with the EML4-ALK fusion. |
URL | 查看原文 |
收录类别 | SCIE |
语种 | 英语 |
WOS研究方向 | Cell Biology |
WOS类目 | Cell Biology |
WOS记录号 | WOS:000649370700001 |
出版者 | SPRINGERNATURE |
原始文献类型 | Article |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/126655 |
专题 | 生命科学与技术学院_博士生 生命科学与技术学院_特聘教授组_季红斌组 生命科学与技术学院_特聘教授组_朱学良组 |
通讯作者 | Yan, Xiumin; Zhu, Xueliang; Ji, Hongbin |
作者单位 | 1.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, State Key Lab Cell Biol, Shanghai, Peoples R China; 2.Univ Chinese Acad Sci, Beijing, Peoples R China; 3.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China; 4.Jinan Univ, Inst Life & Hlth Engn, Guangzhou, Guangdong, Peoples R China; 5.Zhejiang Univ, Life Sci Inst, Hangzhou, Zhejiang, Peoples R China; 6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Hangzhou, Zhejiang, Peoples R China |
通讯作者单位 | 生命科学与技术学院 |
推荐引用方式 GB/T 7714 | Qin, Zhen,Sun, Honghua,Yue, Meiting,et al. Phase separation of EML4-ALK in firing downstream signaling and promoting lung tumorigenesis[J]. CELL DISCOVERY,2021,7(1). |
APA | Qin, Zhen.,Sun, Honghua.,Yue, Meiting.,Pan, Xinwen.,Chen, Liang.,...&Ji, Hongbin.(2021).Phase separation of EML4-ALK in firing downstream signaling and promoting lung tumorigenesis.CELL DISCOVERY,7(1). |
MLA | Qin, Zhen,et al."Phase separation of EML4-ALK in firing downstream signaling and promoting lung tumorigenesis".CELL DISCOVERY 7.1(2021). |
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