WNT morphogens trigger signaling pathways fundamental for embryogenesis, regeneration, and cancer. WNTs are modified with palmitoleate, which is critical for binding Frizzled (FZD) receptors and activating signaling. However, it is unknown how WNTs are released and spread from cells, given their strong lipid-dependent membrane attachment. We demonstrate that secreted FZD-related proteins and WNT inhibitory factor 1 are WNT carriers, potently releasing lipidated WNTs and forming active soluble complexes. WNT release occurs by direct handoff from the membrane protein WNTLESS to the carriers. In turn, carriers donate WNTs to glypicans and FZDs involved in WNT reception and to the NOTUM hydrolase, which antagonizes WNTs by lipid moiety removal. WNT transfer from carriers to FZDs is greatly facilitated by glypicans that serve as essential co-receptors in Wnt signaling. Thus, an extracellular network of carriers dynamically controls secretion, posttranslational regulation, and delivery of WNT morphogens, with important practical implications for regenerative medicine.

WNT 形态发生素触发胚胎发生、再生和癌症的基本信号通路。WNT 用棕榈油酸酯修饰，这对于结合卷曲 （FZD） 受体和激活信号传导至关重要。然而，鉴于 WNT 具有很强的脂质依赖性膜附着，因此尚不清楚 WNT 是如何从细胞中释放和传播的。我们证明分泌的 FZD 相关蛋白和 WNT 抑制因子 1 是 WNT 载体，有效释放脂质化的 WNT 并形成活性可溶性复合物。WNT 释放是通过从膜蛋白 WNTLESS 直接传递给载体来实现的。反过来，载体将 WNT 捐赠给参与 WNT 接收的 glypicans 和 FZD 以及 NOTUM 水解酶，后者通过去除脂质部分来拮抗 WNT。WNT 从载体到 FZD 的转移由作为 Wnt 信号传导中必需的辅助受体的 glypicans 极大地促进。因此，细胞外载体网络动态控制 WNT 形态发生的分泌、翻译后调节和递送，对再生医学具有重要的实际意义。