Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
Mol Cell Biol. 2013 Aug;33(15):2963-75. doi: 10.1128/MCB.01698-12. Epub 2013 May 28.
Wnt signaling has an essential role in embryonic development as well as stem/progenitor cell renewal, and its aberrant activation is implicated in many diseases, including several cancers. β-Catenin is a critical component of Wnt-mediated transcriptional activation. Here we show that ARF6 activation during canonical Wnt signaling promotes the intracellular accumulation of β-catenin via a mechanism that involves the endocytosis of growth factor receptors and robust activation of extracellular signal-regulated kinase (ERK). ERK promotes casein kinase 2-mediated phosphorylation of α-catenin, leading to destabilization of the adherens junctions and a subsequent increase in cytoplasmic pools of active β-catenin and E-cadherin. ERK also phosphorylates LRP6 to amplify the Wnt transduction pathway. The aforementioned Wnt-ERK signaling pathway initiates lumen filling of epithelial cysts by promoting cell proliferation in three-dimensional cell cultures. This study elucidates a mechanism responsible for the switch in β-catenin functions in cell adhesion at the adherens junctions and Wnt-induced nuclear signaling.
Wnt 信号通路在胚胎发育以及干细胞/祖细胞更新中具有重要作用，其异常激活与许多疾病有关，包括多种癌症。β-连环蛋白是 Wnt 介导的转录激活的关键组成部分。在这里，我们发现经典 Wnt 信号转导过程中 ARF6 的激活通过一种涉及生长因子受体内吞和细胞外信号调节激酶（ERK）的强烈激活的机制促进了β-连环蛋白的细胞内积累。ERK 促进钙粘蛋白激酶 2 介导的α-连环蛋白磷酸化，导致黏附连接的不稳定，并随后增加细胞质中活性β-连环蛋白和 E-钙粘蛋白的池。ERK 还磷酸化 LRP6 以放大 Wnt 转导途径。上述 Wnt-ERK 信号通路通过促进三维细胞培养中的细胞增殖来启动上皮囊肿的管腔填充。本研究阐明了负责在黏附连接处β-连环蛋白在细胞黏附中的功能转换以及 Wnt 诱导的核信号转导的机制。
