2. Academic Validation
  3. A molecular mechanism for Wnt ligand-specific signaling

A molecular mechanism for Wnt ligand-specific signaling

  • Science. 2018 Aug 17;361(6403):eaat1178. doi: 10.1126/science.aat1178.
Marie Eubelen 1,  Naguissa Bostaille 1,  Pauline Cabochette 1,  Anne Gauquier 1,  Patricia Tebabi 1,  Andra C Dumitru 2,  Melanie Koehler 2,  Philipp Gut 1,  David Alsteens 2,  Didier Y R Stainier 3,  Abel Garcia-Pino 4 5,  Benoit Vanhollebeke 6 5 7
Affiliations

Affiliations

  • 1 Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles (ULB), Gosselies B-6041, Belgium.
  • 2 NanoBiophysics Laboratory, Louvain Institute of Biomolecular Science and Technology, Université catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
  • 3 Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
  • 4 Laboratory of Cellular and Molecular Microbiology, Department of Molecular Biology, ULB, Gosselies B-6041, Belgium.
  • 5 Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Belgium.
  • 6 Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles (ULB), Gosselies B-6041, Belgium. benoit.vanhollebeke@ulb.ac.be.
  • 7 Center for Microscopy and Molecular Imaging (CMMI), ULB, Gosselies B-6041, Belgium.
PMID: 30026314 DOI: 10.1126/science.aat1178
Abstract

Wnt signaling is key to many developmental, physiological, and disease processes in which cells seem able to discriminate between multiple Wnt ligands. This selective Wnt recognition or "decoding" capacity has remained enigmatic because Wnt/Frizzled interactions are largely incompatible with monospecific recognition. Gpr124 and Reck enable brain endothelial cells to selectively respond to Wnt7. We show that Reck binds with low micromolar affinity to the intrinsically disordered linker region of Wnt7. Availability of Reck-bound Wnt7 for Frizzled signaling relies on the interaction between Gpr124 and Dishevelled. Through polymerization, Dishevelled recruits Gpr124 and the associated Reck-bound Wnt7 into dynamic Wnt/Frizzled/Lrp5/6 signalosomes, resulting in increased local concentrations of Wnt7 available for Frizzled signaling. This work provides mechanistic insights into the Wnt decoding capacities of vertebrate cells and unravels structural determinants of the functional diversification of Wnt family members.

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