From the Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
From the Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
J Biol Chem. 2018 Dec 21;293(51):19710-19724. doi: 10.1074/jbc.RA118.004434. Epub 2018 Oct 25.
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/β-catenin signaling. The hyperactivation of WNT/β-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 β-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 β-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/β-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/β-catenin signaling.
与经典 WNT 糖蛋白结合后,卷曲受体家族(FZDs)和低密度脂蛋白受体相关蛋白 5/6(LRP5/6)在细胞表面发生一系列聚合,引发经典 WNT/β-连环蛋白信号通路。WNT/β-连环蛋白信号通路的过度激活是肿瘤发生的主要原因,但肝癌等肿瘤中的机制仍不清楚。在这里,我们观察到 WNT3A 与卷曲受体竞争性抑制分子分泌型卷曲相关蛋白 2(SFRP2)结合后,在β-连环蛋白依赖性信号中表现出过度活性。为了了解 SFRP2 存在时 FZD 的机制,我们探索了 FZD 如何在没有 WNT 糖蛋白的情况下独立结合和激活 LRP5/6 信号体。我们的研究结果进一步揭示,FZD 和 LRP5/6 的寡聚化可以将细胞质蛋白 Dishevelled 整合到 LRP5/6 信号体中,导致配体非依赖性β-连环蛋白信号的强烈激活。我们提出,除了 WNT 桥接的 FZD-WNT-LRP5/6 蛋白复合物外,WNT 受体的同源和异源寡聚化可能有助于细胞表面 LRP5/6 信号体的形成。值得注意的是,我们在肝癌细胞系 HepG2 中鉴定出四种高表达的 FZD,它们都显著促进了配体非依赖性 LRP5/β-连环蛋白信号。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,LRP5/6 信号体中 FZD 和 LRP5/6 的组成和化学计量可能调节结合的 WNT 糖蛋白的选择,并配置下游的 WNT/β-连环蛋白信号。