Regulation of Wnt Signaling

Regulation of Wnt Signaling

The Wnt signaling pathway is one of the oldest and most universal signaling pathways in the animal kingdom. This pathway is involved in the development of almost every organ in the body and is one of the first signaling pathways to be activated when the sperm fertilizes the egg. Outside of development, Wnt signaling is critically important for generating stem cells that are required for regenerating the lining of the gut or in hair regeneration or in bone growth and repair. Messing with this pathway has serious consequences in development and in the adult. Genetic alterations that keep this pathway constitutively active are at the root cause of many cancers, most notably colorectal cancers.Mutations that activate Wnt signaling within the colon stem cells are the initiating event in 90% of all colorectal cancers. On the opposite side of the coin, genetic alterations that inhibit Wnt signaling are the cause of osteoporosis. The list goes on and on and everyday there are new reports about Wnt signaling in some disease. Check out this link to see how Wnt signaling is involved in disease.

I have been studying Wnt signaling since 1997 (Wnt references) and currently our lab focuses on the regulation of this pathway. Essentially, we want to know how this pathway is controlled. Its involvement in so many things and its long evolutionary history suggests that mechanisms are in place to tightly regulate how much and how long a Wnt signal will last. Similar to driving a car, good control of the gas and brakes is required to get to your destination. Imagine the catastrophe if you jam the gas pedal don’t have any brakes! In essence, this is what is happening in the colorectal cancer stem cells. Using this analogy our lab studies the brakes of the Wnt signaling pathway. We use the early zebrafish embryo to understand how the brakes work normally and then use this information to understand how these brakes fail to stop the activated Wnt signaling that cause cancer. In the following pages we describe in more detail our research program on the regulation of Wnt signaling during development, in disease and in identifying new inhibitors of this pathway.

Wnt Signaling Figure: Normal Wnt Signaling. In its resting, unstimulated state, in which there is no Wnt ligand:

1. An intracellular, constitutively active, destruction complex consisting of Axin, APC, GSK3 and CK1 binds to and phosphorylates β-catenin, resulting in ubiquitin-mediated degradation of β-catenin.
2. The presence of Wnt ligand binding to its receptors, Frizzled and LRP6
   1. initiates activation of the pathway, resulting in activation of the scaffolding protein Dvl.
   2. Activated Dvl inhibits the destruction complex.
   3. This results in accumulation of cytoplasmic β-catenin.
   4. Which translocates into the nucleus
   5. To activate transcription of target genes.
   6. Two universal and obligate targets of the Wnt pathway are nkd1 and axin2.