Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex
Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex
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DOI：
10.1016/j.devcel.2008.05.007
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发表时间：
2008-07-01
影响因子：
11.8
通讯作者：
Sasaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Yamamoto, Shinji;Nishimura, Osamu;Sasaki, Hiroshi
脊椎动物 Wnt 蛋白激活几种不同的途径。 Wnt 配体和卷曲 (Fzd) 受体之间的内在差异，以及途径特异性辅助受体 LRP5/6 和 Ror2 的可用性，都会影响途径选择。在这里，我们发现分泌型糖蛋白 Cthrc1 参与 Wnt 蛋白选择性激活平面细胞极性 (PCP) 通路。尽管 Cthrc1 缺失突变小鼠表现正常，但 PCP 基因 Vangl2 杂合突变的引入导致了 PCP 突变体特征的异常。在 HEK293T 细胞中，Cthrc1 激活 PCP 途径，但抑制经典途径。细胞表面锚定的 Cthrc1 与 Wnt 蛋白、Fzd 蛋白和 Ror2 结合，并通过形成 Cthrc1-Wnt-Fzd/Ror2 复合物增强 Wnt 蛋白和 Fzd/Ror2 的相互作用。与此一致的是，Ror2突变小鼠的内耳也表现出与PCP相关的异常。这些结果表明 Cthrc1 是一种 Wnt 辅因子蛋白，可通过稳定配体-受体相互作用选择性激活 Wnt/PCP 通路。
Vertebrate Wnt proteins activate several distinct pathways. Intrinsic differences among Wnt ligands and Frizzled (Fzd) receptors, and the availability of pathway-specific coreceptors, LRP5/6, and Ror2, affect pathway selection. Here, we show that a secreted glycoprotein, Cthrc1, is involved in selective activation of the planar cell polarity (PCP) pathway by Wnt proteins. Although Cthrc1 null mutant mice appeared normal, the introduction of a heterozygous mutation of a PCP gene, Vangl2, resulted in abnormalities characteristic of PCP mutants. In HEK293T cells, Cthrc1 activated the PCP pathway but suppressed the canonical pathway. Cell-surface-anchored Cthrc1 bound to Wnt proteins, Fzd proteins, and Ror2 and enhanced the interaction of Wnt proteins and Fzd/Ror2 by forming the Cthrc1-Wnt-Fzd/Ror2 complex. Consistent with this, Ror2 mutant mice also showed PCP-related abnormalities in the inner ear. These results suggest that Cthrc1 is a Wnt cofactor protein that selectively activates the Wnt/PCP pathway by stabilizing ligand-receptor interaction.