TAK1 Phosphorylates RASSF9 and Inhibits Esophageal Squamous Tumor Cell Proliferation by Targeting the RAS/MEK/ERK Axis.
TAK1 Phosphorylates RASSF9 and Inhibits Esophageal Squamous Tumor Cell Proliferation by Targeting the RAS/MEK/ERK Axis.
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TAK1 磷酸化 RASSF9 并通过靶向 RAS/MEK/ERK 轴抑制食管鳞状肿瘤细胞增殖
DOI：
10.1002/advs.202001575
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Sun C
中科院分区：
文献类型：
--
作者：
Shi H;Ju Q;Mao Y;Wang Y;Ding J;Liu X;Tang X;Sun C
TGF-β 激活激酶 1 (TAK1) 是一种丝氨酸/苏氨酸激酶，是多种信号传导途径的关键中间体。然而，其在肿瘤发生中的作用仍不清楚。本研究发现食管肿瘤组织和细胞系中TAK1表达量降低。体外实验表明，TAK1 表达敲低可增强食管肿瘤细胞的增殖，TAK1 表达升高可减弱食管肿瘤细胞的增殖。使用皮下肿瘤模型，这些观察结果在体内得到证实。根据免疫共沉淀与质谱联用的结果，Ras 关联域家族 9 (RASSF9) 被确定为 TAK1 的下游靶标。 TAK1 在 S284 处磷酸化 RASSF9，从而导致 RAS 二聚化减少，从而阻断 RAF/MEK/ERK 信号转导。临床调查显示TAK1表达与食管癌患者的生存呈负相关。综上所述，数据表明，TAK1 介导的 RASSF9 Ser284 磷酸化通过抑制 RAS/MEK/ERK 轴负向调节食管肿瘤细胞增殖。食管鳞状肿瘤细胞中TAK1减少，RASSF9与RAS结合并引起RAS二聚化，从而触发RAF/MEK/ERK信号转导和肿瘤细胞增殖。当 TAK1 存在时，它会磷酸化 RASSF9 的丝氨酸 284，这种修饰会破坏 RAS 二聚化，从而导致下游通路和细胞增殖的阻断。
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. 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.
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影响因子：
5.7
作者：
Muratcioglu, Serena;Chavan, Tanmay S.;Freed, Benjamin C.;Jang, Hyunbum;Khavrutskii, Lyuba;Freed, R. Natasha;Dyba, Marzena A.;Stefanisko, Karen;Tarasov, Sergey G.;Gursoy, Attila;Keskin, Ozlem;Tarasova, Nadya I.;Gaponenko, Vadim;Nussinov, Ruth
通讯作者：
Nussinov, Ruth
影响因子：
64.8
作者：
Ishitani, T;Ninomiya-Tsuji, J;Matsumoto, K
通讯作者：
Matsumoto, K
影响因子：
168.9
作者：
Lozano, Rafael;Naghavi, Mohsen;Murray, Christopher J. L.
通讯作者：
Murray, Christopher J. L.
影响因子：
2.6
作者：
Gavin, A. T.;Francisci, S.;Anderson, L. A.
通讯作者：
Anderson, L. A.
RasGRP3将营养应激转导至Notch通路可促进人食管鳞状细胞癌的恶性侵袭
影响因子：
4.2
作者：
Hu, Ge;Zhou, Yuepeng;Chen, Deyu
通讯作者：
Chen, Deyu