Wnt Related Diseases


The Wnt signaling pathway is conserved in all metazoans and plays a crucial role in a plethora of cellular processes by regulating the activity of Wnt intracellular targets. Wnt transcriptional targets vary by the organism and the specific tissue that is targeted by the Wnt signaling. The loss of Wnt signaling components, or failure in the regulation of Wnt signaling can have detrimental effects during both embryonic and postnatal developmental stages. Aberrant Wnt signaling has been associated with numerous diseases and human cancers such as, colorectal, breast, ovarian, and neuroectodermal tumors. The involvement of the Wnt signaling pathway in cancer development is best described for colorectal cancer, where mutations in the tumor suppressor APC (Adenomatous polyposis coli), a Wnt signaling component, result in nuclear accumulation of β-catenin and subsequent transcriptional activation of Wnt target genes, by mimicking ligand mediated Wnt pathway stimulation. Mutations in Wnt signaling components such as β-catenin and Axin proteins, and production defects of Wnts, have been implicated in cellular transformation resulting in tumor formation.

One key component of Wnt signaling is Wls, the dedicated Wnt molecular chaperone. All 19 human Wnts are predicted to be lipidmodified by Porcupine, which has been shown to require modified Wnt interaction with Wls to promote extracellular release. Secreted Wnt can then activate signaling through β-catenin dependent or independent pathways. Wls is indispensible for Wnt secretion. Mutations of Wls that prevent normal Wls protein production result in Wnt accumulation in Wnt-expressing cells. Conditional Wls knock-out studies with the wnt1-Cre mouse have shown that the lack of Wls causes defects in anterior-posterior axis formation. Recently, it has been shown that WLS is overexpressed in brain tumors, indicating that misregulated Wnt signaling is a potential driver of glioma tumourigenesis. Additionally, it has been reported that in colon cancer cells, high levels of WNT and WLS are the main cause of overstimulation of canonical Wnt signaling, even in the presence of APC or β-catenin activating mutations. A recent study suggests overexpression of Wntless could be related to activation of the NF-kB signaling pathway, since there was a positive correlation observed between overexpression of WLS and the activation of the nuclear factor kB signaling members (p65, p50, p52, and RelB) in cancer (HeLa) cells. According to examination of leukemia cells isolated from patient’s bone marrow revealed that overexpression of WLS paired with the activation of canonical Wnt signaling was significantly correlated with the disease relapse and poor survival. Since Wls is a key regulator and the most upstream controller of Wnt secretion, it is a potential candidate for screening various cancer types and a target for therapeutic drug development.

 

Modification of Wnt Proteins

Wnt proteins are defined by sequence and not by functional properties. A typical Wnt protein would contain a signal sequence which is followed by series of cysteines residues which are highly conserved. Wnt proteins are insoluble and hydrophobic in nature as these molecules are palmitoylated. Since the palmitoylation is present on the conserved cysteine, all Wnts carry this modification. Mutant analyses have shown that, treating Wnt with the enzyme acyl protein thioesterase results in loss of hydrophobicity and Wnt becomes inactive. These findings suggest that cysteine is essential for function and the palmitate is critical for signaling. The enzyme responsible for adding the palmitate to Wnts is encoded by the porcupine (por) gene in Drosophila. There is a sequence similarity between porcupine and membrane-bound acyltransferases called mom-1. These enzymes are present in the endoplasmic reticulum (ER) membrane and acylate a variety of substrates. Therefore, it is believed that por encodes for an enzyme that catalyzes the transfer of palmitate onto Wnt.