LRP6 is internalized by Dkk1 to suppress its phosphorylation in the lipid raft and is recycled for reuse
LRP6 is internalized by Dkk1 to suppress its phosphorylation in the lipid raft and is recycled for reuse
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DOI：
10.1242/jcs.058008
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发表时间：
2010-02-01
影响因子：
4
通讯作者：
Kikuchi, Akira
中科院分区：
文献类型：
--
作者：
Sakane, Hiroshi;Yamamoto, Hideki;Kikuchi, Akira
β-连环蛋白介导的Wnt信号传导在动物发育和肿瘤进展中至关重要。低密度脂蛋白受体相关蛋白6（LRP 6）是一种单跨膜Wnt受体，其磷酸化在该信号传导中起着至关重要的作用。Dickkopf 1（Dkk 1）已被证明可以抑制Wnt-β-catenin通路，但其机制尚不清楚。在这里，有证据表明，Wnt 3a依赖的LRP 6磷酸化发生在脂筏和Dkk 1抑制LRP 6和酪蛋白激酶1 γ（CK 1 γ）之间的复合物的形成，从脂筏去除LRP 6。Dkk 1在Rab 5依赖性机制中内化LRP 6，以防止CK 1 γ介导的磷酸化。内化的LRP 6以Rab 11依赖性机制再循环回细胞表面膜，再循环的LRP 6再次对Wnt 3a和Dkk 1作出反应。内化的Dkk 1以Rab 7介导的途径运输并在溶酶体中降解。这些结果表明，Dkk 1诱导LRP 6的内化，以抑制其在脂筏中的磷酸化，并允许LRP 6随后再循环，以便其可以重新用于信号传导。
beta-catenin-mediated Wnt signaling is crucial in animal development and tumor progression. The phosphorylation of low-density lipoprotein receptor-related protein 6 (LRP6), a single-span transmembrane Wnt receptor, plays a vital role in this signaling. Dickkopf1 (Dkk1) has been shown to inhibit the Wnt-beta-catenin pathway, but the mechanism is not yet clear. Here, evidence is presented that Wnt3a-dependent phosphorylation of LRP6 occurs in the lipid raft and that Dkk1 inhibits the formation of a complex between LRP6 and casein kinase 1 gamma (CK1 gamma) by removing LRP6 from the lipid raft. Dkk1 internalized LRP6 in a Rab5-dependent mechanism to prevent phosphorylation mediated by CK1 gamma. The internalized LRP6 was recycled back in a Rab11-dependent mechanism to the cell-surface membrane, and the recycled LRP6 again responded to Wnt3a and Dkk1. Internalized Dkk1 was trafficked in a Rab7-mediated route and degraded in the lysosome. These results suggest that Dkk1 induces the internalization of LRP6 to suppress its phosphorylation in the lipid raft and allows subsequent recycling of LRP6 so that it can be reused for signaling.