In the absence of an active canonical Wnt ligand, β‐catenin is phosphorylated in the cytoplasm by a complex of proteins, the so‐called destruction complex, which includes the serine–threonine kinases Glycogen synthase kinase 3 (Gsk3) and Casein kinase 1 (Ck1), the scaffold protein Axin and the tumor suppressor Adenomatous polyposis coli (APC), leading to proteasomal degradation of β‐catenin and suppression of Wnt/β‐catenin signaling 11. This fine‐tuning can be based on a variety of events including ligand–receptor complex formation, phosphorylation by kinases, adjustment of intracellular β‐catenin levels, and tissue‐specific modulator activities 7, 8, 9, 10. Development of new therapeutic approaches for these diseases necessitates elucidation of the molecular mechanisms underlying fine‐tuning of the pathway at various levels. Mutations in Wnt signaling components and modulators are thus associated with various genetic disorders, cancers, and degenerative diseases 6.
Wnt/β‐catenin signaling, also referred to as the canonical Wnt pathway, plays pivotal roles in regulation of embryonic development, maintenance of tissue homeostasis and regeneration 1, 2, 3, 4, 5. We thus conclude that ordered plasma membrane environments are essential for binding of canonical Wnts to their receptor complexes and downstream signaling activity. 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. 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. 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. Here, we reveal the influence of the immediate plasma membrane environment on the canonical Wnt–receptor interaction. 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.
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