COMPARATIVE CELL BASED FUNCTIONAL ANALYSIS OF KEY WNT/BETA-CATENIN PATHWAY GENES AND GENE MUTATIONS

Abstract

The Wnt/Beta-catenin signaling pathway has many roles including regulation of developmental pathways, cell proliferation, and homeostasis of adult tissues. Wnt/Beta-catenin signaling activity depends on the stability and localization of Beta-catenin in the cell. In the absence of a Wnt-signal, Beta-catenin, which plays an integral role as a cell adhesion adapter protein and as a transcriptional coregulator, is phosphorylated by GSK3 Beta; in a complex with APC, AXIN, and CK1. Phosphorylation promotes ubiquitination of Beta-catenin and subsequent proteasomal degradation. When a Wnt-ligand binds to a Frizzled receptor, a signaling cascade displaces GSK3 Beta from its complex with Beta-catenin allowing Beta-catenin protein to accumulate and translocate to the nucleus. In the nucleus, Beta-catenin activates transcription of its target genes by binding TCF/LEF transcription factors. Aberrant Wnt/Beta-catenin signaling activity leads to misregulation of proliferation and metabolic pathways and has been linked to a number of diseases.