Extracellular AGR2 activates neighboring fibroblasts through endocytosis and direct binding to β-catenin that requires AGR2 dimerization and adhesion domains
Extracellular AGR2 activates neighboring fibroblasts through endocytosis and direct binding to β-catenin that requires AGR2 dimerization and adhesion domains
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细胞外 AGR2 通过胞吞作用并直接结合需要 AGR2 二聚化和粘附结构域的 β-连环蛋白来激活邻近的成纤维细胞
DOI：
10.1016/j.bbrc.2021.08.028
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发表时间：
2021-08-14
影响因子：
3.1
通讯作者：
Li, Dawei
中科院分区：
文献类型：
--
作者：
Merugu, Siva Bharath;Zhou, Bingjie;Li, Dawei
前梯度2（AGR 2）通常在几种类型的癌症中过表达。AGR 2是细胞质的或作为细胞外信号分泌。细胞内AGR 2的性质和在癌症中的作用已经得到了很好的研究，但其细胞外功能在很大程度上是不清楚的。已经显示细胞外AGR 2激活培养物中的内皮细胞和成纤维细胞，但是AGR 2信号传导的机制还没有很好地阐明。在这里，我们报告了肿瘤分泌或外部添加的AGR 2通过内吞作用易位到细胞质中，与β-连环蛋白结合，并进一步共易位到NIH 3 T3成纤维细胞的细胞核中。外部添加的AGR 2也增加了成纤维细胞和癌细胞中β-连环蛋白的表达、稳定性和细胞核中的积累。外部AGR 2挽救了被EGFR抑制剂AG 1478抑制的β-连环蛋白的表达，表明了不依赖于EGFR信号调节β-连环蛋白的替代途径。当将抗AGR 2的单克隆抗体添加到实验中时，这些效应被消除，证实了这些效应仅由AGR 2引起。综上所述，我们的研究结果表明，细胞外AGR 2信号通路涉及内吞介导的细胞转位，直接结合和调节β-catenin核积累。它也是针对肿瘤启动的AGR 2信号传导以形成和维持肿瘤微环境的靶标。(C)2021爱思唯尔公司All rights reserved.
Anterior gradient 2 (AGR2) is often overexpressed in several types of cancer. AGR2 is cytoplasmic or secreted as an extracellular signal. Intracellular AGR2 properties and role in cancer have been well studied, but its extracellular function is largely unclear. It has been shown that extracellular AGR2 activates endothelial cells and fibroblasts in culture, but the mechanism of AGR2 signaling is not well elucidated. Here, we report that tumor secreted or externally added AGR2 translocates into cytoplasm by endocytosis, binds to beta-catenin and further co-translocates to the nucleus in NIH3T3 fibroblasts. Externally added AGR2 also increased beta-catenin expression, stability, and accumulation in the nucleus in both fibroblasts and cancer cells. External AGR2 rescued the expression of fi-catenin, which was suppressed by EGFR inhibitor AG1478 indicating an alternative pathway to regulate beta-catenin independent of EGFR signal. These effects were abolished when a monoclonal antibody against AGR2 was added to the experiments, confirming the effects are caused by AGR2 only. Putting together, our results show that extracellular AGR2 signaling pathway involves endocytosis mediated cellular translocation, direct binding and regulating beta-catenin nuclear accumulation. It is also a target against tumor initiated AGR2 signaling to form and maintain tumor microenvironment. (C) 2021 Elsevier Inc. All rights reserved.