Capurro Mariana I, Xu Ping, Shi Wen, Li Fuchuan, Jia Angela, Filmus Jorge
Division of Molecular and Cell Biology, Sunnybrook Research Institute and Department of Medical Biophysics, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N3M5, Canada.
Dev Cell. 2008 May;14(5):700-11. doi: 10.1016/j.devcel.2008.03.006.
Loss-of-function mutations in glypican-3 (GPC3), one of the six mammalian glypicans, causes the Simpson-Golabi-Behmel overgrowth syndrome (SGBS), and GPC3 null mice display developmental overgrowth. Because the Hedgehog signaling pathway positively regulates body size, we hypothesized that GPC3 acts as an inhibitor of Hedgehog activity during development. Here, we show that GPC3 null embryos display increased Hedgehog signaling and that GPC3 inhibits Hedgehog activity in cultured mouse embryonic fibroblasts. In addition, we report that GPC3 interacts with high affinity with Hedgehog but not with its receptor, Patched, and that GPC3 competes with Patched for Hedgehog binding. Furthermore, GPC3 induces Hedgehog endocytosis and degradation. Surprisingly, the heparan sulfate chains of GPC3 are not required for its interaction with Hedgehog. We conclude that GPC3 acts as a negative regulator of Hedgehog signaling during mammalian development and that the overgrowth observed in SGBS patients is, at least in part, the consequence of hyperactivation of the Hedgehog signaling pathway.
Glypican-3（GPC3）是六种哺乳动物glypicans之一，其功能丧失突变会导致Simpson-Golabi-Behmel过度生长综合征（SGBS），且GPC3基因敲除小鼠表现出发育过度。由于Hedgehog信号通路正向调节体型大小，我们推测GPC3在发育过程中作为Hedgehog活性的抑制剂发挥作用。在此，我们表明GPC3基因敲除胚胎显示出增强的Hedgehog信号，并且GPC3在培养的小鼠胚胎成纤维细胞中抑制Hedgehog活性。此外，我们报告GPC3与Hedgehog以高亲和力相互作用，但不与其受体Patched相互作用，并且GPC3与Patched竞争结合Hedgehog。此外，GPC3诱导Hedgehog内吞和降解。令人惊讶的是，GPC3的硫酸乙酰肝素链对于其与Hedgehog的相互作用并非必需。我们得出结论，GPC3在哺乳动物发育过程中作为Hedgehog信号的负调节因子发挥作用，并且在SGBS患者中观察到的过度生长至少部分是Hedgehog信号通路过度激活的结果。
