Wnt1 and Wnt5a induce cyclin D1 expression through ErbB1 transactivation in HC11 mammary epithelial cells
Wnt1 and Wnt5a induce cyclin D1 expression through ErbB1 transactivation in HC11 mammary epithelial cells
复制标题
DOI：
10.1038/sj.embor.embor735
复制
发表时间：
2003-02-01
期刊：
影响因子：
7.7
通讯作者：
Hynes, NE
中科院分区：
文献类型：
--
作者：
Civenni, G;Holbro, T;Hynes, NE
HC11 乳腺细胞中 Wnt1 和 Wnt5a 的组成型表达导致 TCF 转录活性升高。有趣的是，表达 Wnt 的细胞还表现出 ErbB1 和丝裂原激活蛋白激酶 (MAPK) 的激活，而对照 HC11 细胞则没有。此外，从表达 Wnt 的细胞中收获的条件培养基在添加到对照细胞中时会刺激 ErbB1 和 MAPK 级联。这个过程很快，并且可以被干扰配体结合的 ErbB1 抗体和基质金属蛋白酶 (MMP) 抑制剂阻断。这些结果表明，在乳腺细胞中，Wnt 与其受体 Frizzled (Fz) 结合，可能通过 MMP 介导的可溶性 ErbB1 配体释放来反式激活 ErbB1。重要的是，Wnt 反式激活的 ErbB1 负责 MAPK 激活以及表达 Wnt 的 HC11 细胞中细胞周期蛋白 D1 水平的增加。我们发现 Writs 除了刺激原型 β-连环蛋白/TCF 通路外还反式激活 ErbB1，这可能有助于解释为什么 wnt1 是乳腺中的强癌基因。
Constitutive expression of Wnt1 and Wnt5a in HC11 mammary cells led to elevated TCF transcriptional activity. Intriguingly, Wnt-expressing cells also displayed activation of ErbB1 and mitogen-activated protein kinase (MAPK), in contrast to control HC11 cells, which did not. Furthermore, conditioned media harvested from Wnt-expressing cells stimulated ErbB1 and the MAPK cascade when added to control cells. This process was rapid and could be blocked by an ErbB1 antibody that interferes with ligand binding and by matrix metalloproteinase (MMP) inhibitors. These results suggest that in mammary cells Wnt binding to its receptor, Frizzled (Fz), transactivates ErbB1, probably by MMP-mediated release of soluble ErbB1 ligands. Importantly, Wnt-transactivated ErbB1 was responsible for MAPK activation and the increased levels of cyclin D1 present in the Wnt-expressing HC11 cells. Our finding that Writs transactivate ErbB1 in addition to stimulating the prototypic beta-catenin/TCF pathway may help to explain why wnt1 is a potent oncogene in the mammary gland.