Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jalan Raya Bandung-Sumedang KM. 21, Jatinangor, Jawa Barat 45-363, Indonesia.
Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Department of Pathology, Faculty of Medicine, Sohag University, Nasr City, Eastern Avenue, Sohag 82749, Egypt.
Cell Signal. 2019 Jul;59:24-33. doi: 10.1016/j.cellsig.2019.03.016. Epub 2019 Mar 16.
Transmembrane prostate androgen-induced protein (TMEPAI) is a type I transmembrane protein induced by several intracellular signaling pathways such as androgen, TGF-β, EGF, and Wnt signaling. It has been reported that TMEPAI functions to suppress TGF-β and androgen signaling but here, we report a novel function of TMEPAI in Wnt signaling suppression. First, we show that TMEPAI significantly inhibits TCF/LEF transcriptional activity stimulated by Wnt3A, LiCl, and β-catenin. Mechanistically, TMEPAI overexpression prevented β-catenin accumulation in the nucleus and TMEPAI knockout in triple negative breast cancer cell lines promoted β-catenin stability and nuclear accumulation together with increased mRNA levels of Wnt target genes AXIN2 and c-MYC. The presence of TGF-β type I receptor kinase inhibitor did not affect the enhanced mRNA expression of AXIN2 in TMEPAI knockout cells. These data suggest that TMEPAI suppresses Wnt signaling by interfering with β-catenin stability and nuclear translocation in a TGF-β signaling-independent manner.
跨膜前列腺雄激素诱导蛋白（TMEPAI）是一种 I 型跨膜蛋白，可被多种细胞内信号通路诱导，如雄激素、TGF-β、EGF 和 Wnt 信号通路。已有报道称 TMEPAI 的功能是抑制 TGF-β和雄激素信号，但在这里，我们报告了 TMEPAI 在抑制 Wnt 信号中的一个新功能。首先，我们表明 TMEPAI 可显著抑制 Wnt3A、LiCl 和 β-连环蛋白刺激的 TCF/LEF 转录活性。从机制上讲，过表达 TMEPAI 可防止β-连环蛋白在核内积累，而三阴性乳腺癌细胞系中 TMEPAI 的敲除则促进了β-连环蛋白的稳定性和核内积累，同时 Wnt 靶基因 AXIN2 和 c-MYC 的 mRNA 水平也增加。TGF-β 型 I 受体激酶抑制剂的存在并不影响 TMEPAI 敲除细胞中 AXIN2 的增强 mRNA 表达。这些数据表明，TMEPAI 通过 TGF-β 信号通路独立的方式干扰β-连环蛋白的稳定性和核易位来抑制 Wnt 信号。
