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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



Publication Date





2513 - 2526


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