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Cell Rep. 2018 Oct 9;25(2):339-349.e9. doi: 10.1016/j.celrep.2018.09.045.

A RECK-WNT7 Receptor-Ligand Interaction Enables Isoform-Specific Regulation of Wnt Bioavailability.

Author information

1
Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Department of Molecular and Cellular Physiology, Department of Structural Biology, and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Department of Nuclear Medicine, University Hospital Bonn, 53127 Bonn, Germany.
4
Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8501, Japan.
5
Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: cjkuo@stanford.edu.

Abstract

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.

KEYWORDS:

GPR124; RECK; WNT7; Wnt signaling; blood-brain barrier; central nervous system; endothelial cells

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