German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, Department of Cell and Molecular Biology, University of Heidelberg.
Curr Top Dev Biol. 2011;97:21-53. doi: 10.1016/B978-0-12-385975-4.00008-5.
Wnt signaling is one of the most important developmental signaling pathways that controls cell fate decisions and tissue patterning during early embryonic and later development. It is activated by highly conserved Wnt proteins that are secreted as palmitoylated glycoproteins and act as morphogens to form a concentration gradient across a developing tissue. Wnt proteins regulate transcriptional and posttranscriptional processes depending on the distance of their origin and activate distinct intracellular cascades, commonly referred to as canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) pathways. Therefore, the secretion and the diffusion of Wnt proteins needs to be tightly regulated to induce short- and long-range downstream signaling. Even though the Wnt signaling cascade has been studied intensively, key aspects and principle mechanisms, such as transport of Wnt growth factors or regulation of signaling specificity between different Wnt pathways, remain unresolved. Here, we introduce basic principles of Wnt/Wg signal transduction and highlight recent discoveries, such as the involvement of vacuolar ATPases and vesicular acidification in Wnt signaling. We also discuss recent findings regarding posttranslational modifications of Wnts, trafficking through the secretory pathway and developmental consequences of impaired Wnt secretion. Understanding the detailed mechanism and regulation of Wnt protein secretion will provide valuable insights into many human diseases based on overactivated Wnt signaling.
Wnt 信号通路是最重要的发育信号通路之一，它在早期胚胎和后期发育过程中控制细胞命运决定和组织模式形成。它由高度保守的 Wnt 蛋白激活，这些蛋白作为棕榈酰化糖蛋白分泌，并作为形态发生素在发育组织中形成浓度梯度。Wnt 蛋白根据其起源的距离调节转录和转录后过程，并激活不同的细胞内级联反应，通常称为经典（β-连环蛋白依赖性）和非经典（β-连环蛋白非依赖性）途径。因此，Wnt 蛋白的分泌和扩散需要严格调节，以诱导短程和长程下游信号。尽管 Wnt 信号级联已被深入研究，但关键方面和原则机制，如 Wnt 生长因子的运输或不同 Wnt 途径之间信号特异性的调节，仍然没有得到解决。在这里，我们介绍 Wnt/Wg 信号转导的基本原理，并强调最近的发现，如液泡 ATP 酶和囊泡酸化在 Wnt 信号转导中的参与。我们还讨论了最近关于 Wnt 的翻译后修饰、通过分泌途径运输以及 Wnt 分泌受损的发育后果的发现。理解 Wnt 蛋白分泌的详细机制和调节将为基于过度激活的 Wnt 信号的许多人类疾病提供有价值的见解。
