14.2 : Canonical Wnt Signaling Pathway

Wnt family proteins are secreted, lipid-modified glycoproteins that get their name from a portmanteau of the Wingless gene in Drosophila and the Integrated gene in vertebrates - both of which encode Wnt proteins.

This protein family regulates a conserved signaling pathway that controls numerous critical developmental events in all animals.

For example, Wnt has roles in cell fate determination - whether cells will survive, divide, or undergo apoptosis - as well as cell motility and polarity- and organogenesis and stem cell renewal.

There are 19 different Wnt proteins present in humans that can regulate genes through three different pathways.

In all three of these pathways, the signaling in the target cells is mediated via transmembrane receptors called Frizzled receptors - as well as coreceptors such as low-density lipoprotein related proteins, or LRPs.

The Wnt protein binds to these proteins to form a Wnt-Frizzled-coreceptor complex.

But at this point, the three pathways diverge.

The canonical pathway, known as the Wnt β-catenin pathway regulates the breakdown of the protein β-catenin, which plays an important role in the regulation of gene transcription and is also a crucial part of cadherin-catenin-actin complex during cell-cell adhesion.

In the absence of Wnt signaling, the cytosolic β-catenin is constantly phosphorylated and ubiquitinated by the degradation complex for degradation by the proteasome.

However, the binding of the Wnt protein to the Frizzled and LRP protein interrupts the activity of the degradation complex with the help of a phosphoprotein called dishevelled - which helps in recruiting axin, GSK3, and CK1 - the main components of the degradation complex to the membrane.

This results in increased levels of cytoplasmic β-catenin and its translocation into the nucleus, where it binds to the transcriptional factors of the T-cell family, displacing the Gro repressor and inducing the expression of Wnt target genes.

Two of the most prominent Wnt target genes are cyclin D1 and c-myc. They are both oncogenes, that regulate the stimulation of cell growth and proliferation, as well as cell death.

Their over-expression due to an abnormality in the Wnt signaling pathway can lead to uncontrolled cell growth and proliferation and ultimately progression of cancer.