LRP1 mediates Hedgehog-induced endocytosis of the GPC3-Hedgehog complex
LRP1 mediates Hedgehog-induced endocytosis of the GPC3-Hedgehog complex
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DOI：
10.1242/jcs.098889
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发表时间：
2012-07-15
影响因子：
4
通讯作者：
Filmus, Jorge
中科院分区：
文献类型：
--
作者：
Capurro, Mariana I.;Shi, Wen;Filmus, Jorge
磷脂酰肌醇蛋白聚糖-3（GPC 3）是一种硫酸乙酰肝素（HS）蛋白聚糖，通过糖基磷脂酰肌醇连接与细胞膜结合。这种磷脂酰肌醇蛋白聚糖通过抑制hedgehog（Hh）信号通路来调节胚胎生长。GPC 3结合Hh并与Hh受体Patched（Ptc）竞争Hh结合。Hh与GPC 3的相互作用触发GPC 3-Hh复合物的内吞作用和降解，从而减少可用于结合Ptc的Hh。目前，GPC 3-Hh复合物内化的分子机制仍然未知。在这里，我们表明，低密度脂蛋白受体相关蛋白-1（LRP 1）介导的Hh诱导的GPC 3-Hh复合物的内吞作用，这种内吞作用是必要的Hh抑制活性的GPC 3。此外，我们证明，GPC 3通过其HS链结合到LRP 1，这种相互作用导致GPC 3从脂筏结构域中去除。
Glypican-3 (GPC3) is a heparan sulfate (HS) proteoglycan that is bound to the cell membrane through a glycosylphosphatidylinositol link. This glypican regulates embryonic growth by inhibiting the hedgehog (Hh) signaling pathway. GPC3 binds Hh and competes with Patched (Ptc), the Hh receptor, for Hh binding. The interaction of Hh with GPC3 triggers the endocytosis and degradation of the GPC3-Hh complex with the consequent reduction of Hh available for binding to Ptc. Currently, the molecular mechanisms by which the GPC3-Hh complex is internalized remains unknown. Here we show that the low-density-lipoprotein receptor-related protein-1 (LRP1) mediates the Hh-induced endocytosis of the GPC3-Hh complex, and that this endocytosis is necessary for the Hh-inhibitory activity of GPC3. Furthermore, we demonstrate that GPC3 binds through its HS chains to LRP1, and that this interaction causes the removal of GPC3 from the lipid rafts domains.