CXXC-type zinc finger protein 5 (CXXC5)–Dishevelled (Dvl) protein–protein interaction (CXXC5–Dvl PPI)

CXXC-type zinc finger protein 5 (CXXC5) is a zinc-finger protein that functions as a negative regulator of the Wnt/β-catenin signaling pathway by directly binding to the Dishevelled (Dvl) protein (Kim et al., 2010, DOI: 10.1038/ncb2022). The interaction occurs between the C-terminal Dishevelled-binding motif (DBM) of CXXC5 and the PDZ domain of Dvl, which effectively inhibits the downstream transduction of Wnt signals (Lee et al., 2015, DOI: 10.1038/ncomms8020). This protein-protein interaction (PPI) has emerged as a therapeutic target for conditions where Wnt signaling is suppressed, such as androgenetic alopecia, osteoporosis, and impaired wound healing (Rhee et al., 2017, DOI: 10.1111/jcmm.13339). By disrupting the CXXC5–Dvl interaction using competitive peptides like PTD-DBM or small molecules like KY19382, researchers can restore Wnt/β-catenin signaling, promoting hair follicle regeneration and osteoblast differentiation (Lee et al., 2016, DOI: 10.1002/anie.201600101). The activation of this pathway leads to the stabilization and nuclear translocation of β-catenin, which then triggers the transcription of genes involved in cell proliferation and differentiation. While activating this pathway offers significant regenerative potential, safety concerns primarily involve the risk of oncogenesis, as aberrant Wnt activation is a hallmark of several cancers (Kim et al., 2016, DOI: 10.1016/j.apsb.2016.01.001). Additionally, the challenge of achieving high specificity for the Dvl PDZ domain without affecting other PDZ-containing proteins remains a hurdle in drug development. Current research is focused on topical applications to minimize systemic exposure and potential side effects.

Other names

CXXC5-Dvl interactionCXXC5-DSH interactionCXXC5-PDZ interactionCXXC5-Dvl1 interactionCXXC5-Dvl2 interactionCXXC5-Dvl3 interaction

Inhibition of the CXXC5–Dvl protein-protein interaction to prevent negative regulation of the Wnt/β-catenin pathway, thereby promoting pathway activation.