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Mechanistic differences between LGR4 and LGR5
The receptor LGR4 promotes Wnt signaling in response to the binding of R-spondin ligands (RSPOs) both by inhibiting the activities of the E3 ligases RNF43 and ZNRF3 and by directly stimulating the Wnt signalosome through the scaffold protein IQGAP1. It is thought that LGR5 stimulates Wnt signaling similarly to LGR4 although LGR4 and LGR5 are not functionally equivalent in vivo. By analyzing the interactions of LGR4 and LGR5 with RSPOs, components of the Wnt signalosome, and RNF43 and ZNRF3 in cultured cells, Park et al. found that LGR5 did not bind to RNF43 or ZNRF3 regardless of the presence of RSPOs but did promote Wnt signaling through IQGAP1. They also found that LGR4 interacted with RNF43 or ZNRF3 regardless of the presence of RSPOs. These findings demonstrate that LGR4 and LGR5 potentiate Wnt signaling through distinct mechanisms.
Abstract
LGR4 and LGR5 encode two homologous receptors with critical, yet distinct, roles in organ development and adult stem cell survival. Both receptors are coexpressed in intestinal crypt stem cells, bind to R-spondins (RSPOs) with high affinity, and potentiate Wnt–β-catenin signaling, presumably by the same mechanism: forming RSPO-bridged complexes with the E3 ligases RNF43 and ZNRF3 to inhibit ubiquitylation of Wnt receptors. However, direct evidence for RSPO-bound, full-length LGR5 interacting with these E3 ligases in whole cells has not been reported, and only LGR4 is essential for the self-renewal of intestinal stem cells. Here, we examined the mechanisms of action of LGR4 and LGR5 in parallel using coimmunoprecipitation, proximity ligation, competition binding, and time-resolved FRET assays in whole cells. Full-length LGR4 formed a tight complex with ZNRF3 and RNF43 even without RSPO, whereas LGR5 did not interact with either E3 ligase with or without RSPO. Domain-swapping experiments with LGR4 and LGR5 revealed that the seven-transmembrane domain of LGR4 conferred interaction with the E3 ligases. Native LGR4 and LGR5 existed as dimers on the cell surface, and LGR5 interacted with both FZD and LRP6 of the Wnt signalosome to enhance LRP6 phosphorylation and potentiate Wnt–β-catenin signaling. These findings provide a molecular basis for the weaker activity of LGR5 in the potentiation of Wnt signaling that may underlie the distinct roles of LGR4 and LGR5 in organ development, as well as the self-renewal and fitness of adult stem cells.
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