24.3:
Non-Canonical Wnt Signaling Pathways
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 non-canonical Wnt pathways are both Beta-catenin independent.
The second Wnt pathway, known as the planar cell polarity pathway, is facilitated by the Rho or Rac family of GTPases.
With the help of disheveled protein, they modulate the activity of Rho and JNK which are both involved in the coordination of cell polarization and migration during embryo development.
Finally, in the Wnt-Calcium pathway, the interaction of the Wnt-Frizzled-coreceptor complex with the disheveled protein transmits the signal to phospholipase C which in turn leads to the release of intracellular calcium ions from the endoplasmic reticulum.
The correct balance of calcium levels in cells is critical and any mutations affecting the regulation of calcium levels can affect multiple functions in animals – including the development of a healthy prenatal heart and muscular tissue.
24.3:
Non-Canonical Wnt Signaling Pathways
Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The non-canonical Wnt pathways, also known as β-catenin independent pathways, are diverse and less characterized than the canonical Wnt/β-catenin dependent signaling pathway.
Planar-cell polarity pathway
The Wnt-Frizzled PCP signaling pathway was initially discovered through genetic studies in Drosophila. But it has also been found to be functional in vertebrates, where it is required in many developmental processes that need directional information, such as the development of skin, the orientation of body hair, the polarization of cells in the oviduct and respiratory tract, etc. However, the regulation of the PCP pathway is conserved from Drosophila to mammals.
The individual cell polarity is established by the segregation of the PCP protein complexes on the opposite sides of each cell. In contrast, the PCP complexes present on the same side of the membrane but on adjacent cells stabilize each other. This is essential for propagating and establishing the same spatial symmetry from cell to cell.
Wnt/Ca2+ signaling pathway
Amongst the 19 Wnt genes present in vertebrates, Wnt5a is a 'classical' non-canonical Wnt signal transducer that activates the calcium signaling pathway in the presence of a suitable receptor of the Frizzled family. However, Wnt5a can also bind to other membrane-bound receptors such as Ror1/2 of the tyrosine kinase family to activate the Ca2+/CaMKII pathway in the cell.
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