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

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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Availability
  • Blood-Brain Barrier
  • Female
  • Frizzled Receptors / genetics
  • Frizzled Receptors / metabolism*
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Male
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • Wnt3A Protein / genetics
  • Wnt3A Protein / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • ADGRA2 protein, human
  • CTNNB1 protein, human
  • Frizzled Receptors
  • GPI-Linked Proteins
  • RECK protein, human
  • Receptors, G-Protein-Coupled
  • WNT3A protein, human
  • WNT7A protein, human
  • Wnt Proteins
  • Wnt3A Protein
  • beta Catenin