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Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Author(s): Andrey Voronkov and Stefan Krauss

Affiliation: SFI-CAST Biomedical Innovation Center, Unit for Cell Signaling, Oslo University Hospital,Forskningsparken, Gaustadalleén 21, 0349, Oslo, Norway.

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.

Keywords: β-catenin, cancer, drug discovery, small molecule inhibitors, stem cells, Wnt

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Article Details

VOLUME: 19
ISSUE: 4
Page: [634 - 664]
Pages: 31
DOI: 10.2174/1381612811306040634