The role of glypican-3 in the regulation of body size and cancer
The role of glypican-3 in the regulation of body size and cancer
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DOI：
10.4161/cc.7.18.6672
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发表时间：
2008-09-15
期刊：
影响因子：
4.3
通讯作者：
Capurro, Mariana
中科院分区：
文献类型：
--
作者：
Filmus, Jorge;Capurro, Mariana
磷脂酰肌醇蛋白聚糖是硫酸乙酰肝素蛋白聚糖家族，其成员通过糖基磷脂酰肌醇 (GPI) 锚结合到细胞表面。 GPC3（六种哺乳动物磷脂酰肌醇蛋白聚糖之一）的功能丧失突变会导致 Simson-Golabi-Behmel 综合征。这是一种以产前和产后过度生长、广泛的内脏和骨骼异常以及胚胎肿瘤发生风险增加为特征的疾病。 GPC3 缺失的小鼠也表现出明显的过度生长。我们最近报道，GPC3 在发育过程中充当 Hedgehog 信号传导的负调节因子，并且由于功能性 GPC3 缺乏而导致的过度生长至少部分归因于 Hedgehog 信号传导的过度激活。在这里，我们讨论了导致我们假设 GPC3 可能是 Hedgehog 信号传导的负调节因子的基本原理，并推测了我们的发现对 GPC3 在某些癌症类型中的作用的影响。我们还讨论了我们最近的实验结果，这些实验研究了核心蛋白、硫酸乙酰肝素链和 GPI 锚在 GPC3 功能中的作用。最后，我们对 GPC3 的组织特异性功能提出了解释。
Glypicans are a family of heparan sulfate proteoglycans whose members are bound to the cell surface by a glycosylphosphatidylinositol (GPI) anchor. Loss-of-function mutations in GPC3, one of the six mammalian glypicans, causes the Simson-Golabi-Behmel Syndrome. This is a disorder characterized by pre- and post-natal overgrowth, a broad spectrum of visceral and skeletal abnormalities, and an increased risk for the development of embryonic tumors. GPC3-null mice also display significant overgrowth. We have recently reported that GPC3 acts as a negative regulator of Hedgehog signaling during development, and that the overgrowth caused by the lack of functional GPC3 is due, at least in part, to the hyperactivation of Hedgehog signaling. Here we discuss the rationale that led us to hypothesize that GPC3 could be a negative regulator of Hedgehog signaling, and speculate about the implications of our discovery regarding the role of GPC3 in some cancer types. We also discuss our recent results of experiments that investigated the role of the core protein, the heparan sulfate chains, and the GPI anchor in GPC3 function. Finally, we propose an explanation for the tissue-specific function of GPC3.