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While the cytosolic events of Wnt/β-catenin signaling (canonical Wnt signaling) pathway have been widely studied, only little is known about the molecular mechanisms involved in Wnt binding to its receptors at the plasma membrane. Here, we reveal the influence of the immediate plasma membrane environment on the canonical Wnt-receptor interaction. While the receptors are distributed both in ordered and disordered environments, Wnt binding to its receptors selectively occurs in more ordered membrane environments which appear to cointernalize with the Wnt-receptor complex. Moreover, Wnt/β-catenin signaling is significantly reduced when the membrane order is disturbed by specific inhibitors of certain lipids that prefer to localize at the ordered environments. Similarly, a reduction in Wnt signaling activity is observed in Niemann-Pick Type C disease cells where trafficking of ordered membrane lipid components to the plasma membrane is genetically impaired. We thus conclude that ordered plasma membrane environments are essential for binding of canonical Wnts to their receptor complexes and downstream signaling activity.

Original publication




Journal article


The FEBS journal

Publication Date





2513 - 2526


MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, UK.


Cells, Cultured, Cell Line, Tumor, CHO Cells, Cell Membrane, Membrane Microdomains, Embryo, Nonmammalian, Animals, Animals, Genetically Modified, Zebrafish, Humans, Cricetulus, Niemann-Pick Diseases, Cytoskeletal Proteins, Zebrafish Proteins, Luminescent Proteins, Recombinant Fusion Proteins, Genes, Reporter, Wnt Proteins, HEK293 Cells, Low Density Lipoprotein Receptor-Related Protein-6, Wnt3 Protein, Wnt3A Protein, Wnt Signaling Pathway, Receptors, Wnt