Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium
Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium
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DOI：
10.1073/pnas.1510167112
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发表时间：
2015-08-04
影响因子：
11.1
通讯作者：
Matozaki, Takashi
中科院分区：
文献类型：
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作者：
Murata, Yoji;Kotani, Takenori;Matozaki, Takashi
肠上皮细胞有助于调节哺乳动物的肠道免疫，但这种调节的详细分子机制仍然很大程度上未知。胃癌相关蛋白酪氨酸磷酸酶 1（SAP-1，也称为 PTPRH）是一种受体型蛋白酪氨酸磷酸酶，特异性定位于胃肠道上皮细胞刷状缘的微绒毛。在这里，我们发现，在白细胞介素（IL）-10缺陷型小鼠（炎症性肠病模型）中消除SAP-1会导致结肠炎严重程度显着增加，这与结肠中各种细胞因子和趋化因子的mRNA上调有关。癌胚抗原相关细胞粘附分子 (CEACAM) 20（一种 Ig 超家族的肠道微绒毛特异性跨膜蛋白）的酪氨酸磷酸化在 SAP-1 缺陷动物的肠上皮中大大增加，表明该蛋白是 SAP-1 的底物。蛋白酪氨酸激酶 c-Src 对 CEACAM20 进行酪氨酸磷酸化，以及随后 CEACAM20 与脾酪氨酸激酶 (Syk) 的关联，通过激活核因子 kappa B (NF-kappa B) 促进培养细胞中 IL-8 的产生。此外，还发现 SAP-1 和 CEACAM20 通过胞外域相互作用形成复合物。因此，SAP-1 和 CEACAM20 构成了肠道上皮细胞促进肠道免疫的调节系统。
Intestinal epithelial cells contribute to regulation of intestinal immunity in mammals, but the detailed molecular mechanisms of such regulation have remained largely unknown. Stomach-cancer-associated protein tyrosine phosphatase 1 (SAP-1, also known as PTPRH) is a receptor-type protein tyrosine phosphatase that is localized specifically at microvilli of the brush border in gastrointestinal epithelial cells. Here we show that SAP-1 ablation in interleukin (IL)-10-deficient mice, a model of inflammatory bowel disease, resulted in a marked increase in the severity of colitis in association with up-regulation of mRNAs for various cytokines and chemokines in the colon. Tyrosine phosphorylation of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 20, an intestinal microvillus-specific transmembrane protein of the Ig superfamily, was greatly increased in the intestinal epithelium of the SAP-1-deficient animals, suggesting that this protein is a substrate for SAP-1. Tyrosine phosphorylation of CEACAM20 by the protein tyrosine kinase c-Src and the consequent association of CEACAM20 with spleen tyrosine kinase (Syk) promoted the production of IL-8 in cultured cells through the activation of nuclear factor-kappa B (NF-kappa B). In addition, SAP-1 and CEACAM20 were found to form a complex through interaction of their ectodomains. SAP-1 and CEACAM20 thus constitute a regulatory system through which the intestinal epithelium contributes to intestinal immunity.