Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Molecular and Cellular Physiology, Department of Structural Biology, and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell Rep. 2018 Oct 9;25(2):339-349.e9. doi: 10.1016/j.celrep.2018.09.045.
WNT7A and WNT7B control CNS angiogenesis and blood-brain barrier formation by activating endothelial Wnt/β-catenin signaling. The GPI-anchored protein RECK and adhesion G protein-coupled receptor GPR124 critically regulate WNT7-specific signaling in concert with FZD and LRP co-receptors. Here, we demonstrate that primarily the GPR124 ectodomain, but not its transmembrane and intracellular domains, mediates RECK/WNT7-induced canonical Wnt signaling. Moreover, RECK is the predominant binding partner of GPR124 in rat brain blood vessels in situ. WNT7A and WNT7B, but not WNT3A, directly bind to purified recombinant soluble RECK, full-length cell surface RECK, and the GPR124:RECK complex. Chemical cross-linking indicates that RECK and WNT7A associate with 1:1 stoichiometry, which stabilizes short-lived, active, monomeric, hydrophobic WNT7A. In contrast, free WNT7A rapidly converts into inactive, hydrophilic aggregates. Overall, RECK is a selective WNT7 receptor that mediates GPR124/FZD/LRP-dependent canonical Wnt/β-catenin signaling by stabilizing active cell surface WNT7, suggesting isoform-specific regulation of Wnt bioavailability.
WNT7A 和 WNT7B 通过激活内皮细胞 Wnt/β-连环蛋白信号通路来控制中枢神经系统血管生成和血脑屏障的形成。GPI 锚定蛋白 RECK 和黏附 G 蛋白偶联受体 GPR124 与 FZD 和 LRP 共受体协同调控 WNT7 特异性信号通路。在此，我们证明主要是 GPR124 的胞外结构域，而不是其跨膜和细胞内结构域，介导 RECK/WNT7 诱导的经典 Wnt 信号通路。此外，RECK 是原位大鼠脑血管中 GPR124 的主要结合伴侣。WNT7A 和 WNT7B，但不是 WNT3A，可直接与纯化的重组可溶性 RECK、全长细胞表面 RECK 和 GPR124:RECK 复合物结合。化学交联表明 RECK 和 WNT7A 以 1:1 的化学计量比结合，这稳定了短暂的、活性的、单体的、疏水性的 WNT7A。相比之下，游离的 WNT7A 会迅速转化为无活性的、亲水性的聚集体。总的来说，RECK 是一种选择性的 WNT7 受体，通过稳定活性的细胞表面 WNT7 来介导 GPR124/FZD/LRP 依赖性经典 Wnt/β-连环蛋白信号通路，提示 Wnt 生物利用度的同工型特异性调控。
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