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bioRxiv · 10.1101/2025.11.24.690281

The Actin regulator Mena promotes Wnt signalosome endocytosis and Wnt signalling.

Wu, S.-y.·Moreno, M. M.·Noble, A.·Azwan, A. H.·Guille, M.·Liu, K. J.·Krause, M.
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Abstract

Wnt signaling controls embryonic development and tissue maintenance. Endocytosis of Wnt-receptors is required for signalling, yet uptake mechanisms remain poorly understood. Here, we identify the actin regulator and Ena/VASP protein, Mena, as a key mediator. Upon Wnt stimulation, Mena redistributes from focal adhesions to signalosomes, Wnt-receptor clusters. Mena directly binds Wnt-coreceptors LRP5/6 in a phosphorylation-dependent manner increasing Wnt signal transduction. Sequestration of Ena/VASP proteins impedes in vivo Wnt activation driving Xenopus embryonic development. We resolve previous controversies by showing that Wnt3a triggers rapid Clathrin-Mediated and Fast Endophilin-Mediated LRP6 endocytosis at low concentrations sufficient for Wnt activation. This efficient endocytosis requires Ena/VASP proteins and is specifically promoted by Mena. Our results suggest Mena as a crucial mediator of Wnt signalosome endocytosis thus promoting canonical Wnt signalling.

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Wu, S.-y., Moreno, M. M., Noble, A., Azwan, A. H., Guille, M., Liu, K. J., Krause, M.. 2025-11-25. The Actin regulator Mena promotes Wnt signalosome endocytosis and Wnt signalling.. https://doi.org/10.1101/2025.11.24.690281

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