Department of Cell and Developmental Biology, Program in Developmental Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
J Cell Sci. 2022 Feb 1;135(3). doi: 10.1242/jcs.259405. Epub 2022 Feb 3.
The extracellular distribution of secreted Wnt proteins is crucial for their ability to induce a response in target cells at short and long ranges to ensure proper development. Wnt proteins are evolutionarily conserved ligands that are lipid-modified, and their hydrophobic nature interferes with their solubility in the hydrophilic extracellular environment. This raises the question of how Wnt proteins spread extracellularly despite their lipid modifications, which are essential for both their secretion and function. Seminal studies on Drosophila Wingless (Wg), a prototypical Wnt, have discovered multiple mechanisms by which Wnt proteins spread. A central theme emerges from these studies: the Wnt lipid moiety is shielded from the aqueous environment, allowing the ligands to spread and remain viable for signaling. Wnt distribution in vivo is primarily facilitated by glypicans, which are cell-surface heparan sulfate proteoglycans, and recent studies have further provided mechanistic insight into how glypicans facilitate Wnt distribution. In this Review, we discuss the many diverse mechanisms of Wnt distribution, with a particular focus on glypican-mediated mechanisms.
Wnt 蛋白的细胞外分布对于它们在短距离和长距离范围内诱导靶细胞产生反应的能力至关重要，以确保正常的发育。Wnt 蛋白是经过进化保守修饰的配体，其疏水性会干扰它们在亲水性细胞外环境中的溶解度。这就提出了一个问题，即尽管 Wnt 蛋白经过脂质修饰，对于它们的分泌和功能都是必不可少的，但它们如何在细胞外扩散。对果蝇 Wingless（Wg）的开创性研究发现了多种 Wnt 蛋白扩散的机制。这些研究得出一个核心主题：Wnt 的脂质部分被屏蔽在水相环境之外，使配体能够扩散并保持信号传递的活力。Wnt 在体内的分布主要是通过糖蛋白来实现的，糖蛋白是细胞表面的硫酸乙酰肝素蛋白聚糖，最近的研究进一步提供了关于糖蛋白如何促进 Wnt 分布的机制见解。在这篇综述中，我们讨论了 Wnt 分布的许多不同机制，特别关注糖蛋白介导的机制。
