细胞生物学
内吞作用
生物
Wnt信号通路
斑马鱼
干细胞
干瘪的
内体
LRP6型
信号转导
受体
生物化学
细胞内
基因
作者
Nicky Nguyen,Kelsey A Carpenter,Jessica Ensing,Carla Gilliland,Emma Rudisel,Emily M. Mu,Kate E. Thurlow,Timothy J. Triche,Stephanie Grainger
出处
期刊:Science Signaling
[American Association for the Advancement of Science (AAAS)]
日期:2024-04-16
卷期号:17 (832)
标识
DOI:10.1126/scisignal.adf4299
摘要
Cell-to-cell communication through secreted Wnt ligands that bind to members of the Frizzled (Fzd) family of transmembrane receptors is critical for development and homeostasis. Wnt9a signals through Fzd9b, the co-receptor LRP5 or LRP6 (LRP5/6), and the epidermal growth factor receptor (EGFR) to promote early proliferation of zebrafish and human hematopoietic stem cells during development. Here, we developed fluorescently labeled, biologically active Wnt9a and Fzd9b fusion proteins to demonstrate that EGFR-dependent endocytosis of the ligand-receptor complex was required for signaling. In human cells, the Wnt9a-Fzd9b complex was rapidly endocytosed and trafficked through early and late endosomes, lysosomes, and the endoplasmic reticulum. Using small-molecule inhibitors and genetic and knockdown approaches, we found that Wnt9a-Fzd9b endocytosis required EGFR-mediated phosphorylation of the Fzd9b tail, caveolin, and the scaffolding protein EGFR protein substrate 15 (EPS15). LRP5/6 and the downstream signaling component AXIN were required for Wnt9a-Fzd9b signaling but not for endocytosis. Knockdown or loss of EPS15 impaired hematopoietic stem cell development in zebrafish. Other Wnt ligands do not require endocytosis for signaling activity, implying that specific modes of endocytosis and trafficking may represent a method by which Wnt-Fzd specificity is established.
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