Binding of canonical Wnt ligands to their receptor complexes occurs in ordered plasma membrane environments

Abstract

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.

Polarity-Sensitive Probes for Superresolution Stimulated Emission Depletion Microscopy

“…Protein functionality may be modulated by the state of the lipid order of its immediate membrane environment ( 7 , 41 ). Therefore, it is crucial to be able to determine lipid packing around specific proteins, which requires simultaneous labeling and observation of the proteins (e.g., using GFP) and of polarity-sensitive dyes.…”

“…For example, lipid-lipid and lipid-protein interactions facilitate the segregation of plasma membrane molecules into clusters or nanodomains that constitute catalytic platforms for a myriad of activities such as cellular signaling ( 1 , 2 ). Lateral heterogeneity in lipid order, i.e., how the packing of lipids varies over space, and how this is involved in molecular segregation, is particularly of interest because membrane order may modulate protein functionality ( 3 , 4 , 5 , 6 , 7 ). Saturated lipids can be packed relatively more tightly and form ordered membrane environments in contrast to unsaturated lipids that yield less ordered (i.e., more disordered) membranes.…”

Model membrane systems to reconstitute immune cell signaling

“…One of the most critical properties to take into consideration for modeling key biological membranes, such as the PM, is membrane fluidity. Diffusivity of the molecules residing in the PM of eukaryotic cells is key for their function [10,11]. From yeast to mammals, sterols and acyl chain unsaturation are key factors of cellular membranes modulating membrane fluidity.…”

Functional link between plasma membrane spatiotemporal dynamics, cancer biology, and dietary membrane-altering agents

“…With respect to membrane order, Wnt/β-catenin signaling transduction is thought to initiate from raft domains [132] and is modulated by various key lipid raft components (Fig. 2b, Wnt signaling).…”

“…3a) [152]. As discussed above, multiple signaling pathways, as well as several of their effectors, have been reported to occur in lipid raft domains, including EGFR/Ras, Wnt/β-catenin, insulin receptor, and T cell and B cell receptor signaling [115, 132, 153–158]. Moreover, it has been demonstrated that multiple effectors associated with these pathways require proper membrane organization, i.e., the formation of nanoclusters, in order to signal efficiently (Fig.…”