Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding
Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding
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DOI：
10.1016/j.devcel.2008.03.006
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发表时间：
2008-05-01
影响因子：
11.8
通讯作者：
Filmus, Jorge
中科院分区：
文献类型：
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作者：
Capurro, Mariana I.;Xu, Ping;Filmus, Jorge
glypican-3 （GPC3）是六种哺乳动物glypican之一，其功能缺失突变可导致Simpson-Golabi-Behmel过度生长综合征（SGBS）， GPC3缺失小鼠表现出发育性过度生长。由于Hedgehog信号通路正向调节体型，我们假设GPC3在发育过程中起到抑制Hedgehog活性的作用。在这里，我们发现GPC3缺失的胚胎显示出增加的Hedgehog信号，并且GPC3在培养的小鼠胚胎成纤维细胞中抑制了Hedgehog活性。此外，我们报道了GPC3与Hedgehog基因的高亲和力相互作用，而不是与其受体Patched蛋白相互作用，并且GPC3与Patched蛋白相互竞争以结合Hedgehog基因。此外，GPC3诱导Hedgehog基因内吞和降解。令人惊讶的是，GPC3的硫酸肝素链并不是它与Hedgehog相互作用所必需的。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，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。
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.