WNT-induced association of Frizzled and LRP6 is not sufficient for the initiation of WNT/β-catenin signaling

Jan Hendrik Voss, Zsombor Koszegi, Yining Yan, Emily Shorter, Lukas Grätz, Johanna T. Lanner, Davide Calebiro and Gunnar Schulte ()
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Jan Hendrik Voss: Sec. Receptor Biology & Signaling
Zsombor Koszegi: University of Birmingham
Yining Yan: Sec. Receptor Biology & Signaling
Emily Shorter: Sec. Molecular Muscle Physiology & Pathophysiology
Lukas Grätz: Sec. Receptor Biology & Signaling
Johanna T. Lanner: Sec. Molecular Muscle Physiology & Pathophysiology
Davide Calebiro: University of Birmingham
Gunnar Schulte: Sec. Receptor Biology & Signaling

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The Wingless/Int-1 (WNT) signaling network is essential to orchestrate central physiological processes such as embryonic development and tissue homeostasis. In the currently held tenet, WNT/β-catenin signaling is initiated by WNT-induced recruitment of Frizzleds (FZDs) and LRP5/6 followed by the formation of a multiprotein signalosome complex. Here, we use bioluminescence resonance energy transfer (BRET) to show that different WNT paralogs dynamically trigger FZD-LRP6 association. While WNT-induced receptor interaction was independent of C-terminal LRP6 phosphorylation, it was allosterically modulated by binding of the phosphoprotein Dishevelled (DVL) to FZD. WNT-16B emerged as a ligand of particular interest, as it efficiently promoted FZD-LRP6 association but, unlike WNT-3A, did not lead to WNT/β-catenin signaling. Transcriptomic analysis further revealed distinct transcriptional fingerprints of WNT-3A and WNT-16B stimulation in HEK293 cells. Additionally, single-molecule tracking demonstrated that, despite increasing FZD5 and LRP6 confinement, WNT-16B stimulation did not result in formation of higher-order receptor clusters, in contrast to WNT-3A. Our results suggest that FZD-WNT-LRP5/6 complex formation alone is not sufficient for the initiation of WNT/β-catenin signaling. Instead, we propose a two-step model, where initial ligand-induced FZD-LRP6 association must be followed by receptor clustering into higher-order complexes and subsequent phosphorylation of LRP6 for efficient activation of WNT/β-catenin signaling.

Date: 2025
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DOI: 10.1038/s41467-025-60096-7

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