Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/β-catenin pathway
Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/β-catenin pathway
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卷曲和低密度脂蛋白受体相关蛋白 5/6 的寡聚启动经典 WNT/β-连环蛋白途径的细胞内信号传导
DOI：
10.1074/jbc.ra118.004434
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发表时间：
2018-12-21
影响因子：
4.8
通讯作者：
Gan, Xiaoqing
中科院分区：
文献类型：
--
作者：
Hua, Yue;Yang, Yilin;Gan, Xiaoqing
卷曲家族受体（FZD）和低密度脂蛋白受体相关蛋白5/6（LRP 5/6）与经典WNT糖蛋白结合后，在细胞表面发生一系列聚合反应，引发经典WNT/β-连环蛋白信号传导。WNT/β-catenin信号通路的过度激活是肿瘤发生的主要原因，但在肝癌等肿瘤中的机制尚不清楚。在此，我们观察到WNT 3A在与FZD的竞争性抑制分子分泌的卷曲相关蛋白2（SFRP 2）结合后表现出过度活跃的连环蛋白依赖性信号传导。为了理解FZD在SFRP 2存在下的机制，我们探索了FZD如何独立于WNT糖蛋白结合和激活LRP 5/6信号体。我们的研究结果进一步揭示了FZD和LRP 5/6的寡聚化可以将胞质蛋白Dishevelled整合到LRP 5/6信号体中，导致配体非依赖性连环蛋白信号的强烈激活。我们提出，除了WNT桥接的FZD-WNT-LRP 5/6蛋白复合物，WNT受体的同源和异源寡聚化可能有助于在细胞表面形成LRP 5/6信号体。值得注意的是，我们在肝癌细胞系HepG 2中鉴定了四种高表达的FZD，所有这些FZD均显著促进配体非依赖性LRP 5/β-连环蛋白信号传导。由于FZD在许多肿瘤中异位表达，我们的发现可能为肿瘤病理学提供新的视角。此外，我们的研究结果表明，LRP 5/6信号体内FZD和LRP 5/6的组成和化学计量可以调节结合WNT糖蛋白的选择并配置下游WNT/β-catenin信号传导。
Upon binding to the canonical WNT glycoproteins, Frizzled family receptors (FZDs) and low-density lipoprotein receptor-related protein 5/6 (LRP5/6) undergo a series of polymerizations on the cell surface that elicit canonical WNT/-catenin signaling. The hyperactivation of WNT/-catenin signaling is the major cause of tumorigenesis, but the mechanism in tumors such as hepatoma remains unclear. Here, we observed that WNT3A manifested the hyperactivity in -catenin-dependent signaling after binding to FZD's competitive inhibitory molecule secreted Frizzled-related protein 2 (SFRP2). To understand the mechanism of FZDs in the presence of SFRP2, we explored how FZDs can bind and activate the LRP5/6 signalosome independently of WNT glycoproteins. Our findings further revealed that oligomerizations of FZDs and LRP5/6 can integrate the cytoplasmic protein Dishevelled into the LRP5/6 signalosome, resulting in a robust activation of ligand-independent -catenin signaling. We propose that besides WNT-bridged FZD-WNT-LRP5/6 protein complexes, the homo- and hetero-oligomerizations of WNT receptors may contribute to the formation of the LRP5/6 signalosome on the cell surface. Of note, we identified four highly expressed FZDs in the hepatoma cell line HepG2, all of which significantly promoted ligand-independent LRP5/-catenin signaling. As FZDs are ectopically expressed in numerous tumors, our findings may provide a new perspective on tumor pathologies. Furthermore, the results in our study suggest that the composition and stoichiometry of FZDs and LRP5/6 within the LRP5/6 signalosome may tune the selection of bound WNT glycoproteins and configure downstream WNT/-catenin signaling.