RNF186/EPHB2 Axis Is Essential in Regulating TNF Signaling for Colorectal Tumorigenesis in Colorectal Epithelial Cells
RNF186/EPHB2 Axis Is Essential in Regulating TNF Signaling for Colorectal Tumorigenesis in Colorectal Epithelial Cells
复制标题
DOI：
10.4049/jimmunol.2200229
复制
发表时间：
2022-09
期刊：
影响因子：
--
通讯作者：
Huazhi Zhang;Zhihui Cui;Ting Pan;Huijun Hu;Ruirui He;Ming Yi;Wanwei Sun;Ru Gao;Heping Wang;Xiaojian Ma;Qianwen Peng;Xiong Feng;Shuyan Liang;Yanyun Du;Chenhui Wang
中科院分区：
文献类型：
--
作者：
Huazhi Zhang;Zhihui Cui;Ting Pan;Huijun Hu;Ruirui He;Ming Yi;Wanwei Sun;Ru Gao;Heping Wang;Xiaojian Ma;Qianwen Peng;Xiong Feng;Shuyan Liang;Yanyun Du;Chenhui Wang
受体酪氨酸激酶EPHB 2（EPH受体B2）在许多人类癌症类型中高度表达，特别是在胃肠道癌症，如结肠直肠癌中。在许多癌症类型中已经鉴定出EPHB 2基因的几种编码突变，这表明EPHB 2在癌发生中起关键作用。然而，EPHB 2在肿瘤发生中的确切作用机制仍不清楚。在这项研究中，我们发现EPHB 2是必需的肿瘤坏死因子诱导的信号激活和促炎细胞因子的产生在结直肠上皮细胞。从机制上讲，在TNF刺激后，EPHB 2被其E3连接酶RNF 186泛素化。然后，泛素化的EPHB 2招募并进一步磷酸化TAB 2的9个酪氨酸位点，这是TAB 2和TAK 1之间的结合的关键步骤。由于RNF 186基因敲除的结肠直肠上皮细胞中TNF信号传导的缺陷，与野生型对照小鼠相比，RNF 186基因敲除小鼠中结肠炎推进的结肠直肠癌模型的表型显著降低。此外，我们发现在一个结直肠癌家族中鉴定的EPHB 2基因突变是一种功能获得性突变，与野生型EPHB 2相比，该突变促进了TNF信号转导激活。我们提供的证据表明，EPHB 2-RNF 186-TAB 2-TAK 1信号级联在结直肠上皮细胞中TNF介导的信号转导和结直肠癌的发生中起着重要作用，这可能为治疗结直肠癌提供潜在的靶点。关键点RNF 186和EPHB 2是TNF诱导的信号通路激活所必需的。大肠癌衍生的EPHB 2（D862 N）是一种功能获得性突变体。
The receptor tyrosine kinase EPHB2 (EPH receptor B2) is highly expressed in many human cancer types, especially in gastrointestinal cancers, such as colorectal cancer. Several coding mutations of the EPHB2 gene have been identified in many cancer types, suggesting that EPHB2 plays a critical role in carcinogenesis. However, the exact functional mechanism of EPHB2 in carcinogenesis remains unknown. In this study, we find that EPHB2 is required for TNF-induced signaling activation and proinflammatory cytokine production in colorectal epithelial cells. Mechanistically, after TNF stimulation, EPHB2 is ubiquitinated by its E3 ligase RNF186. Then, ubiquitinated EPHB2 recruits and further phosphorylates TAB2 at nine tyrosine sites, which is a critical step for the binding between TAB2 and TAK1. Due to defects in TNF signaling in RNF186-knockout colorectal epithelial cells, the phenotype of colitis-propelled colorectal cancer model in RNF186-knockout mice is significantly reduced compared with that in wild-type control mice. Moreover, we find that a genetic mutation in EPHB2 identified in a family with colorectal cancer is a gain-of-function mutation that promoted TNF signaling activation compared with wild-type EPHB2. We provide evidence that the EPHB2-RNF186-TAB2-TAK1 signaling cascade plays an essential role in TNF-mediated signal transduction in colorectal epithelial cells and the carcinogenesis of colorectal cancer, which may provide potential targets for the treatment of colorectal cancer. Key Points RNF186 and EPHB2 are required for TNF-induced signaling pathway activation. Colorectal cancer–derived EPHB2 (D862N) is a gain-of-function mutant.