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bioRxiv · 10.1101/2025.10.09.681388

Deciphering the Interaction Between Dvl2 and Profilin2: Effector Molecules of Non-Canonical Wnt Signaling

Das, S.·MAITI, S.
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Abstract

Wnt signalling is a cornerstone of embryonic development, orchestrating critical processes such as body axis formation, gastrulation, and organogenesis through conserved canonical and non-canonical pathways. Dishevelled (Dvl), a central mediator of these pathways, contains conserved DIX, PDZ, and DEP domains, along with an extreme-C-terminus. Recent studies suggest that the extreme-C-terminus regulates non-canonical Wnt signalling via an autoinhibitory interaction with the PDZ domain. Non-canonical Wnt signalling branches into the planar cell polarity (PCP) and Wnt/Ca{superscript 2} pathways. Profilin, a monomeric actin-binding protein, has been implicated in PCP signalling through Daam1-mediated actin polymerization, whereas its silencing disrupts the Wnt/Ca{superscript 2} pathway in a Daam1-independent manner, pointing to a role for profilin upstream of Daam1. In this study, we identify a novel interaction between Dvl2 and profilin2. Co-localization and in vitro pull-down assays demonstrate that profilin2 directly interacts with Dvl2. Furthermore, our study reveals profilin2 binds specifically to the extreme-C-terminus of Dvl2, beyond the polyproline motif, without engaging the PDZ or DEP domains. This challenges the conventional view of profilin-polyproline interactions and highlights the existence of previously unrecognized molecular determinants. Moreover, we show that Dvl2 adopts an autoinhibited conformation through intramolecular binding of its extreme-C-terminus to the PDZ domain. Remarkably, profilin2 retains its binding ability even in this autoinhibited state. Together, these findings uncover a previously unrecognized profilin2-Dvl2 interaction and provide new mechanistic insights into the molecular regulation of non-canonical Wnt signalling.

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Das, S., MAITI, S.. 2025-10-10. Deciphering the Interaction Between Dvl2 and Profilin2: Effector Molecules of Non-Canonical Wnt Signaling. https://doi.org/10.1101/2025.10.09.681388

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