The significance of the Wnt pathway in the pathology of human cancers

Abstract

The wingless-type (Wnt) signalling transduction pathway is essentially a network of a number of separate but interacting pathways. Specific Wnt ligands bind to their target 'frizzled' membrane receptor and interfere with the multi-protein destruction complex, resulting in downstream activation of gene transcription by beta-catenin. Simplistically, the multi-protein destruction complex involves Axin and APC serving as scaffolds binding both beta-catenin and GSK3, to facilitate phosphorylation of beta-catenin by GSK-3beta. Phosphorylated beta-catenin is degraded in proteasomes by the ubiquination machinery. Unphosphorylated beta-catenin accumulates and associates with nuclear transcription factors leading to the eventual transcription and expression of target genes such as c-myc, c-jun, Fra and cyclin D1. There are several regulatory mechanisms for the down-regulation of the Wnt/beta-catenin signal, perhaps reflecting the pivotal nature of the pathway and the detrimental consequences of inappropriate activation. There has been intense investigation into the role of Wnt genes in human cancer. Although no documentation is made of any mutation or amplification of genes encoding Wnt ligands or receptors linked to human cancer to date, several components of the Wnt pathway have been implicated in carcinogenesis, especially APC and beta-catenin.