Question

Read the paper Targeting Wnt Signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms and then answer the following questions.

What role does Wnt play in normal colon activity?

Answer 1

Wnt signaling controls the level of the key modulator β-catenin for signal transduction through processes involving phosphorylation and ubiquitin-mediated degradation which maintains the intestinal homeostasis. This is regulated by the cytoplasmic β-catenin destruction complex, which consists of the core proteins AXIN, adenomatous polyposis coli (APC), casein kinase 1 (CK1), and glycogen synthase kinase 3 (GSK3). In the absence of Wnt, β-catenin is phosphorylated by CK1 and GSK3 in the complex, which is followed by recruitment of the E3 ligase β-TrCP to the complex for ubiquitination and subsequent proteasomal degradation. Upon Wnt ligand engagement to the receptors Frizzled (FZD) and low-density lipoprotein-related protein 5/6 (LRP5/6), the β-catenin destruction complex is recruited to the membrane, whereas β-TrCP is dissociated from the complex (71). This is achieved by a scaffold protein Dishevelled (DVL) in the cytosol that transduces extracellular Wnt signals from receptors to downstream effectors. DVL has the ability to bind to FZD receptor and AXIN protein via its PDZ and DIX domain, respectively, thus facilitating the interaction between the AXIN complex and the Wnt receptors. The DVL-AXIN interaction has been reported to inhibit the destruction complex by interfering with AXIN oligomerization via the DIX domain, whereas DVL polymerization is also believed to enhance Wnt receptor signalosomes. As a consequence, the complex-bound β-catenin is no longer ubiquitinated or degraded, leading to complex saturation and inhibition. This results in accumulation of free β-catenin in the cytoplasm and its subsequent nuclear translocation. In the nucleus, β-catenin displaces the repressor Groucho from T cell factor (TCF)/lymphoid enhancer-binding factor (LEF) transcription factors. β-Catenin/TCF/LEF, together with other coactivators, form an active transcriptional complex, leading to the expression of Wnt target genes.