Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
J Cell Sci. 2010 Feb 1;123(Pt 3):360-8. doi: 10.1242/jcs.058008. Epub 2010 Jan 5.
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 1gamma (CK1gamma) by removing LRP6 from the lipid raft. Dkk1 internalized LRP6 in a Rab5-dependent mechanism to prevent phosphorylation mediated by CK1gamma. 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.
β-连环蛋白介导的 Wnt 信号通路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（LRP6）是一种单跨膜 Wnt 受体，其磷酸化在该信号通路中起着至关重要的作用。Dickkopf1（Dkk1）已被证明可抑制 Wnt-β-连环蛋白通路，但具体机制尚不清楚。本文提供的证据表明，LRP6 在脂筏中发生 Wnt3a 依赖性磷酸化，而 Dkk1 通过将 LRP6 从脂筏中去除来抑制 LRP6 与酪蛋白激酶 1γ（CK1γ）之间的复合物形成，从而抑制 Wnt-β-连环蛋白通路。Dkk1 通过 Rab5 依赖性机制内化 LRP6，以防止 CK1γ介导的磷酸化。内化的 LRP6 通过 Rab11 依赖性机制在循环中重新返回细胞膜，并且重新循环的 LRP6 再次对 Wnt3a 和 Dkk1 作出反应。内化的 Dkk1 通过 Rab7 介导的途径运输，并在溶酶体中降解。这些结果表明，Dkk1 诱导 LRP6 的内化，以抑制其在脂筏中的磷酸化，并允许随后 LRP6 的循环利用，以便可将其重新用于信号转导。
