TAK1 Phosphorylates RASSF9 and Inhibits Esophageal Squamous Tumor Cell Proliferation by Targeting the RAS/MEK/ERK Axis. Issue 5 (6th January 2021)

• Record Type: Journal Article
• Authors: Shi, Hui; Ju, Qianqian; Mao, Yinting; Wang, Yuejun; Ding, Jie; Liu, Xiaoyu; Tang, Xin; Sun, Cheng
• Is Part Of: Advanced science. Volume 8:Issue 5(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-01-06
• Subjects: cell proliferation -- ERK -- esophageal squamous tumor -- MEK -- RASSF9 -- TAK1; Science -- Periodicals; 505
• DOI: 10.1002/advs.202001575
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: TGF‐ β ‐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. Abstract : TAK1 is decreased in esophageal squamous tumor cells, RASSF9 binds to RAS and causes RAS dimerization, which triggers RAF/MEK/ERK signal transduction and tumor cell proliferation. In the presence of TAK1, it phosphorylates RASSF9 at Serine284 and this modification disrupts RAS dimerization, leading to a blockade of downstream pathway and cell proliferation.