Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
Laboratory for Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan.
Commun Biol. 2022 May 5;5(1):421. doi: 10.1038/s42003-022-03370-4.
The Wnt signaling pathway plays a critical role in the developmental and physiological processes of metazoans. We previously reported that the Frizzled4 (FZD4) linker domain plays an important role in Norrin binding and signaling. However, the question remains whether the FZD linker contributes to Wnt signaling in general. Here, we show that the FZD linker is involved in Wnt binding and affects downstream Wnt signaling. A FZD4 chimera, in which the linker was swapped with that of the non-canonical receptor FZD6, impairs the binding with WNT3A and suppresses the recruitment of LRP6 and Disheveled, resulting in reduced canonical signaling. A similar effect was observed for non-canonical signaling. A FZD6 chimera containing the FZD1 linker showed reduced WNT5A binding and impaired signaling in ERK, JNK, and AKT mediated pathways. Altogether, our results suggest that the FZD linker plays an important role in specific Wnt binding and intracellular Wnt signaling.
Wnt 信号通路在后生动物的发育和生理过程中起着关键作用。我们之前报道过，卷曲蛋白 4（FZD4）连接域在诺林结合和信号转导中发挥重要作用。然而，目前仍不清楚 FZD 连接域是否普遍参与 Wnt 信号转导。在这里，我们表明 FZD 连接域参与 Wnt 结合并影响下游 Wnt 信号转导。FZD4 嵌合体中，连接域与非经典受体 FZD6 的连接域交换，会损害与 WNT3A 的结合，并抑制 LRP6 和 Disheveled 的募集，从而导致经典信号转导减少。对于非经典信号转导也观察到类似的效果。含有 FZD1 连接域的 FZD6 嵌合体显示 WNT5A 结合减少，并在 ERK、JNK 和 AKT 介导的途径中信号转导受损。总之，我们的结果表明，FZD 连接域在特定的 Wnt 结合和细胞内 Wnt 信号转导中发挥重要作用。
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