期刊
ADVANCED SCIENCE
卷 8, 期 5, 页码 -出版社
WILEY
DOI: 10.1002/advs.202001575
关键词
cell proliferation; ERK; esophageal squamous tumor; MEK; RASSF9; TAK1
资金
- National Key Research and Development Program of China [2017YFA0701304]
- National Natural Science Foundation of China [81770841, 81970747, 81771999, 81971761, 81701222]
- Project of Six Kinds of Talents Summit of Jiangsu Province [SWYY-051]
- Postdoctoral Science Foundation of China [2018M632337]
- Scientific Program of Nantong City [MS12018065, MS32017011, XG202006-4]
The study reveals that TAK1 downregulation in esophageal tumors inhibits cell proliferation by phosphorylating RASSF9 and blocking the RAS/MEK/ERK axis, suggesting a potential therapeutic target for esophageal cancer treatment.
TGF-beta-activated kinase 1 (TAK1), a serine/threonine kinase, is a key intermediate in several signaling pathways. However, its role in tumorigenesis is still not understood well. In this study, it is found that TAK1 expression decreases in esophageal tumor tissues and cell lines. In vitro experiments demonstrate that proliferation of esophageal tumor cells is enhanced by knockdown of TAK1 expression and attenuated by elevated expression of TAK1. Using a subcutaneous tumor model, these observations are confirmed in vivo. Based on the results from co-immunoprecipitation coupled with mass spectrometry, Ras association domain family 9 (RASSF9) is identified as a downstream target of TAK1. TAK1 phosphorylates RASSF9 at S284, which leads to reduced RAS dimerization, thereby blocking RAF/MEK/ERK signal transduction. Clinical survey reveals that TAK1 expression is inversely correlated with survival in esophageal cancer patients. Taken together, the data reveal that TAK1-mediated phosphorylation of RASSF9 at Ser284 negatively regulates esophageal tumor cell proliferation via inhibition of the RAS/MEK/ERK axis.
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