24.2:
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.
24.2:
Canonical Wnt Signaling Pathway
The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which results in tumor formation in mice. Consequently, this gene family was named "Wnt" – a portmanteau of the wingless and integrated gene names.
The Wnt Signaling Mechanism
The Wnt proteins, secreted from the signaling cell, activate Frizzled receptors on the target cell via paracrine or autocrine signaling. The signaling pathway can subsequently proceed via three different pathways. In a nutshell, unlike the canonical Wnt signaling pathway that is β-catenin dependent, the non-canonical pathways are β-catenin independent and use different secondary messengers. Nevertheless, according to recent discoveries, these pathways are not autonomous and have considerable overlap and crosstalk between them.
Wnt Signaling Functions and Associated Diseases
The Wnt protein is evolutionarily conserved in all animals. It plays a central role in mediating intercellular communication during embryonic development, as well as adult tissue homeostasis. Given the crucial role of Wnt signaling in developmental patterns such as cell differentiation, polarization, and migration, the association of the pathway with cancer progression is predictable. Aberrant Wnt signaling has long been implicated as the primary cause of colorectal cancers.
Due to the vital role of Wnt signaling in the development of the nervous system and its prominence at the synapse, there is recent evidence that supports its role in the aging brain – and even Alzheimer's Disease. Additionally, dysregulation of the Wnt pathway is linked to bone and cardiovascular diseases.
Suggested Reading
- Morgan R., Ankrah R., El-Tanani S., et al. Wnt Signaling as a Therapeutic Target in Cancer and Metastasis. Introduction to Cancer Metastasis. Pages 375-394 (2017)
- Komiya Y. and Habas R. Wnt signal transduction pathways. Organogenesis, 4(2): 68–75 (2008) DOI: 10.4161/org.4.2.5851