Engrailed 2 triggers the activation of multiple phosphorylation-induced signaling pathways in both transcription-dependent and -independent manners

被引:1
作者
Cao, Yong [1 ,2 ]
Jiang, Jie [1 ]
Song, Xueqin [1 ,2 ]
Wang, Xiaoyan [1 ,2 ]
Huang, Fang [1 ,2 ]
Li, Yan [1 ,2 ]
Tang, Li [1 ,2 ]
Li, Mingying [1 ,2 ]
Chen, Zhuang [1 ,2 ]
Chen, Feng [1 ,2 ]
Wan, Haisu [1 ,2 ,3 ,4 ]
机构
[1] Southwest Med Univ, Affiliated Hosp, Expt Med Ctr, Luzhou 646000, Sichuan, Peoples R China
[2] Luzhou Key Lab Mol Canc, Luzhou 646000, Sichuan, Peoples R China
[3] Metab Vasc Dis Key Lab Sichuan Prov, Luzhou 646000, Sichuan, Peoples R China
[4] Southwest Med Univ, Affiliated Hosp, Expt Med Ctr, 25 Taiping St, Luzhou 646000, Sichuan, Peoples R China
关键词
Engrailed; 2; Esophageal squamous cell carcinoma; Protein phosphorylation modification; Homeobox genes; CANCER; EXPRESSION; GENES;
D O I
10.1016/j.bbrc.2023.09.039
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Homeodomain (HD)-containing proteins are typically recognized as transcription factors. Engrailed 2 (EN2) is an HD-containing protein that is highly expressed in various types of cancers, however, the mechanism underlying the biological function of EN2 is not fully understood. Here, we report a transcription-independent function of EN2 in addition to its role as a transcription factor. EN2 expression leads to the activation of multiple signaling pathways mediated by phosphorylation cascades. A phosphoproteomic analysis revealed that the phosphorylation status of numerous protein sites was altered after EN2 is expressed. Notably, EN2 was shown to interact with a myriad of proteins implicated in phosphorylation signaling cascades, as determined by immunoprecipitation-mass spectrometry (IP-MS). We validated the interaction between EN2 and B55 alpha, the regulatory subunit of the PP2A-B55 alpha complex, and confirmed that the phosphatase activity of the complex was suppressed by EN2 binding. To target EN2-induced malignancy, two kinds of small molecules were utilized to inhibit the EN2activated NF-kappa B and AKT signaling pathways. A clear synergistic effect was observed when the activation of the two pathways was simultaneously blocked. Collectively, the data show that EN2 functions in a transcriptionindependent manner in addition to its role as a transcription factor. This finding may have therapeutic implications in treating esophageal squamous cell carcinoma (ESCC).
引用
收藏
页码:127 / 134
页数:8
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