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Novel Mechanisms of Wnt Pathway Modulation

Year: 2026
Type: other
Abstract: The proper regulation of Wnt signaling is critical for normal development and Dishevelled-1 (DVL1) is a central mediator of multiple branches of Wnt pathway activation. While DVL1 is mutated in congenital disorders and its expression increases significantly in cancers, DVL1 is the least studied and least understood of the DVL paralogs. A major goal of this proposal is to define the role of DVL1 in mediating Wnt signaling across multiple pathophysiological contexts in which it has been implicated and elucidate how it contributes to epigenetic regulation and partners with novel interacting transcription factors (TFs) recently discovered. It is unknown how DVL1 regulates multiple branches of Wnt signaling that are perturbed in cancer, but the least about is known about how it regulates b-catenin-independent pathways, a major focal point in this revised proposal. While over a dozen different Wnt pathway modulators including Frizzled neutralizing antibodies, peptide inhibitors, and small molecules inhibitors which exert their influence upstream of DVL1 are in clinical trials, how these agents influence DVL1 function has not been investigated. We will address these critical questions. The rationale for poposed experiments is based on published DVL1 ChIP-seq and RNA-seq datasets and recent experiments involving proximity labeling coupled with LC-MS/MS analyses which identify novel DVL1-interacting TFs. We have identified novel roles of nuclear DVL1, show it associates with TFs not previously known, and show for the first time that it regulates tumor growth. In this proposal we will define the role of nuclear DVL1 and how it partners with TFs to regulate the epigenome. First, we will elucidate how DVL1 is targeted to genomic loci in Aim 1. Second, we will determine how activation of upstream signaling pathways regulate DVL1 binding to gene promoters and enhancers in Aim 2. Third, we will define how DVL1 regulates cell physiology and pathophysiology associated with its dysfunctional regulation across multiple in vivo models. Together, completion of these studies will provide significant insight regarding the mechanism by which altered DVL1 expression may contribute to congenital disorders, cellular dysfunction, and tumor progression. It will address long-standing key knowledge gaps and define entirely new mechanisms of DVL1 regulation involving the recently discovered nuclear roles of DVL1.
DOI: 10.48321/d11fb40ce9
Author: Kevin Pruitt
Language: English
Open Access status: green
OpenAlex ID: W7162185204
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