Tsao Hsi-En, Ho Mitchell
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, United States of America.
Proteoglycan Res. 2025 Apr;3(2). doi: 10.1002/pgr2.70029. Epub 2025 May 13.
Glypicans (GPCs) are a family of cell surface proteoglycans involved in multiple signaling pathways that regulate cell fate and proliferation. They share a characteristic structure composed of a core protein with two or more heparan sulfate chains and a glycosyl-phosphatidylinositol anchor that attaches them to the cell membrane. Aberrant expression of certain glypicans such as GPC1, GPC2, and GPC3 has been found in multiple types of cancer and causes the dysregulation of Wnt, hedgehog, and other signaling pathways, making them emerging targets for cancer immunotherapy. The molecular mechanism by which glypicans interact with signaling factors will provide insights for the development of cancer therapeutics. However, the structural complexes of human glypicans with Wnt and other key signaling factors remain unsolved. In this brief review, we analyze the current protein structural evidence for glypicans, with an emphasis on their interaction with Wnt, in an effort to provide insights to understand the molecular mechanisms by which glypicans play positive or negative roles in Wnt signaling in cancer and to discuss their translational potentials.
磷脂酰肌醇蛋白聚糖（GPCs）是一类细胞表面蛋白聚糖家族，参与多种调节细胞命运和增殖的信号通路。它们具有共同的特征结构，由一个带有两条或更多硫酸乙酰肝素链的核心蛋白和一个将其锚定在细胞膜上的糖基磷脂酰肌醇组成。已发现某些磷脂酰肌醇蛋白聚糖（如GPC1、GPC2和GPC3）在多种癌症中异常表达，并导致Wnt、刺猬等信号通路失调，使其成为癌症免疫治疗的新兴靶点。磷脂酰肌醇蛋白聚糖与信号因子相互作用的分子机制将为癌症治疗药物的开发提供思路。然而，人类磷脂酰肌醇蛋白聚糖与Wnt及其他关键信号因子的结构复合物仍未得到解析。在这篇简短的综述中，我们分析了目前关于磷脂酰肌醇蛋白聚糖的蛋白质结构证据，重点是它们与Wnt的相互作用，以期深入了解磷脂酰肌醇蛋白聚糖在癌症Wnt信号通路中发挥正性或负性作用的分子机制，并探讨它们的转化潜力。
