Wnt/beta-catenin signaling and small molecule inhibitors - PubMed (original) (raw)

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Wnt/beta-catenin signaling and small molecule inhibitors

Andrey Voronkov et al. Curr Pharm Des. 2013.

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Abstract

Wnt/β-catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/β-catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, β-catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where β-catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where β-catenin levels are regulated and the nucleus where β-catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of β-catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellular β- catenin levels. However, β-catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/β-catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of β-catenin at its various locations provides alternative points for therapeutic interventions.

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Figures

Fig. (1)

Fig. (1)

Simplified schematic representation of drug targets (yellow stars) in Wnt/β-catenin-mediated signaling. Four key aspects that regulate β-catenin-mediated signaling are highlighted: the destruction complex, the Wnt/β-catenin signalosome, cadherin junctions, and the hypoxia sensing system Hif-1α (hipoxia induced factor 1β). Proteins that directly interact with Wnt/β-catenin are marked as colored structures, other proteins are marked as circles.

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