Glypican-3 binds to Frizzled and plays a direct role in the stimulation of canonical Wnt signaling
Glypican-3 binds to Frizzled and plays a direct role in the stimulation of canonical Wnt signaling
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DOI：
10.1242/jcs.140871
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发表时间：
2014-04-01
影响因子：
4
通讯作者：
Filmus, Jorge
中科院分区：
文献类型：
--
作者：
Capurro, Mariana;Martin, Tonya;Filmus, Jorge
Glypcan-3(GPC3)是一种结合在细胞表面的蛋白多糖。它在大多数肝细胞癌中表达，但在正常肝细胞中不表达。GPC3通过促进规范的Wnt信号促进肝癌生长。由于Glypicans与Wnts相互作用，有人认为这些蛋白多糖通过增加细胞膜上Wnt的数量来刺激信号传递，从而促进该生长因子与其信号受体Frizzled.的相互作用。然而，在这项研究中，我们证明了GPC3在Wnt信号的刺激中起着更直接的作用。具体地说，我们发现，除了与Wnt相互作用外，GPC3和FrizzledGPC3还通过GPC3的糖胺多聚糖链直接相互作用，表明这种Glypcan刺激Wnt和FrizzledGPC3之间形成信号复合体。与此一致，我们表明WNT在细胞膜上的结合触发了包括WNT、FrizzledGPC3在内的复合体的内吞作用。GPC6(GPC6)抑制典型的Wnt信号转导，尽管它在细胞膜上与Wnt结合，这一发现为我们的模型提供了额外的支持。
Glypican-3 (GPC3) is a proteoglycan that is bound to the cell surface. It is expressed by most hepatocellular carcinomas (HCCs) but not by normal hepatocytes. GPC3 stimulates HCC growth by promoting canonical Wnt signaling. Because glypicans interact with Wnts, it has been proposed that these proteoglycans stimulate signaling by increasing the amount of Wnt at the cell membrane, thus facilitating the interaction of this growth factor with its signaling receptor, Frizzled. However, in this study, we demonstrate that GPC3 plays a more direct role in the stimulation of Wnt signaling. Specifically, we show that, in addition to interacting with Wnt, GPC3 and Frizzled interact directly through the glycosaminoglycan chains of GPC3, indicating that this glypican stimulates the formation of signaling complexes between Wnt and Frizzled. Consistent with this, we show that the binding of Wnt at the cell membrane triggers the endocytosis of a complex that includes Wnt, Frizzled and GPC3. Additional support for our model is provided by the finding that glypican-6 (GPC6) inhibits canonical Wnt signaling, despite the fact that it binds to Wnt at the cell membrane.