Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of β-catenin signaling
Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of β-catenin signaling
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DOI：
10.1016/j.devcel.2008.04.015
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发表时间：
2008-07-01
影响因子：
11.8
通讯作者：
Kikuchi, Akira
中科院分区：
文献类型：
--
作者：
Yamamoto, Hideki;Sakane, Hiroshi;Kikuchi, Akira
Wnt和Dickkopf （Dkk）在Wnt信号通路中拮抗调节β -连环蛋白的稳定；然而，其分子机制尚不清楚。在本研究中，我们发现Wnt3a。平行作用诱导低密度脂蛋白受体相关蛋白6 （LRP6）的小窝蛋白依赖性内化，以及LRP6的磷酸化和Axin在细胞膜表面向LRP6募集。LRP6的磷酸化和内化相互独立发生，两者都是β -连环蛋白积累所必需的。相反，抑制wnt3a依赖性β -连环蛋白稳定化的Dkk1诱导LRP6内化网格蛋白。敲低网格蛋白可抑制dkk1依赖性Wnt3a反应的抑制。此外，Dkk1减少了LRP6在与小窝蛋白相关的脂质筏分数中的分布。这些结果表明，Wnt3a和Dkk1分别将LRP6分流到不同的内化途径，以激活和抑制β -连环蛋白信号传导。
Wnt and Dickkopf (Dkk) regulate the stabilization of beta-catenin antagonistically in the Wnt signaling pathway; however, the molecular mechanism is not clear. In this study, we found that Wnt3a. acts in parallel to induce the caveolin-dependent internalization of low-density-lipoprotein receptor-related protein 6 (LRP6), as well as the phosphorylation of LRP6 and the recruitment of Axin to LRP6 on the cell surface membrane. The phosphorylation and internalization of LRP6 occurred independently of one another, and both were necessary for the accumulation of beta-catenin. In contrast, Dkk1, which inhibits Wnt3a-dependent stabilization of beta-catenin, induced the internalization of LRP6 with clathrin. Knockdown of clathrin suppressed the Dkk1-dependent inhibition of the Wnt3a response. Furthermore, Dkk1 reduced the distribution of LRP6 in the lipid raft fraction where caveolin is associated. These results indicate that Wnt3a and Dkk1 shunt LRP6 to distinct internalization pathways in order to activate and inhibit the beta-catenin signaling, respectively.