Dkk1 stabilizes Wnt co-receptor LRP6: implication for Wnt ligand-induced LRP6 down-regulation.
Dkk1 stabilizes Wnt co-receptor LRP6: implication for Wnt ligand-induced LRP6 down-regulation.
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DOI：
10.1371/journal.pone.0011014
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发表时间：
2010-06-08
期刊：
影响因子：
3.7
通讯作者：
Bu G
中科院分区：
文献类型：
--
作者：
Li Y;Lu W;King TD;Liu CC;Bijur GN;Bu G
低密度脂蛋白受体相关蛋白-6（LRP 6）是经典Wnt信号传导的必需辅助受体。Dickkopf 1（Dkk 1）是一种主要的分泌型Wnt信号传导拮抗剂，以高亲和力结合LRP 6，并阻止响应Wnt的卷曲-Wnt-LRP 6复合物的形成。以前的研究表明，Dkk 1促进LRP 6内化和降解时，它与细胞表面受体Kremen形成三元复合物。在本研究中，我们发现转染Dkk 1诱导LRP 6积累，同时抑制Wnt/LRP 6信号传导。用Dkk 1条件培养基或重组Dkk 1蛋白处理稳定LRP 6，半衰期延长，并诱导LRP 6在细胞表面和内体中积累。我们还证明了Kremen 2共表达消除了Dkk 1对LRP 6积累的影响，表明Kremen 2的作用优于Dkk 1对LRP 6的调节。此外，我们发现Wnt 3A处理诱导LRP 6下调，这一效应与Wnt/LRP 6信号衰减有关，并且Dkk 1处理阻断Wnt 3A诱导的LRP 6下调。最后，我们发现LRP 6周转被小窝介导的内吞作用的抑制剂阻断。我们的研究结果揭示了Dkk 1在阻止Wnt配体诱导的LRP 6下调中的新作用，并为我们理解Dkk 1在Wnt/LRP 6信号转导中的功能做出了重要贡献。
The low density lipoprotein receptor-related protein-6 (LRP6) is an essential co-receptor for canonical Wnt signaling. Dickkopf 1 (Dkk1), a major secreted Wnt signaling antagonist, binds to LRP6 with high affinity and prevents the Frizzled-Wnt-LRP6 complex formation in response to Wnts. Previous studies have demonstrated that Dkk1 promotes LRP6 internalization and degradation when it forms a ternary complex with the cell surface receptor Kremen. In the present study, we found that transfected Dkk1 induces LRP6 accumulation while inhibiting Wnt/LRP6 signaling. Treatment with Dkk1-conditioned medium or recombinant Dkk1 protein stabilized LRP6 with a prolonged half-life and induces LRP6 accumulation both at the cell surface and in endosomes. We also demonstrated that Kremen2 co-expression abrogated the effect of Dkk1 on LRP6 accumulation, indicating that the effect of Kremen2 is dominant over Dkk1 regulation of LRP6. Furthermore, we found that Wnt3A treatment induces LRP6 down-regulation, an effect paralleled with a Wnt/LRP6 signaling decay, and that Dkk1 treatment blocked Wnt3A-induced LRP6 down-regulation. Finally, we found that LRP6 turnover was blocked by an inhibitor of caveolae-mediated endocytosis. Our results reveal a novel role for Dkk1 in preventing Wnt ligand-induced LRP6 down-regulation and contribute significantly to our understanding of Dkk1 function in Wnt/LRP6 signaling.
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