JUN 08, 2017 5:37 PM PDT

Important Component of Sonic Hedgehog Pathway is ID'ed

WRITTEN BY: Carmen Leitch

Researchers have revealed new details about a cellular signaling cascade that has been under intense study in part because of its many links to human disease, published in Cell Reports. The cascade, a pathway called Sonic Hedgehog, has a role in developmental disorders as well as cancer. The investigators are hopeful that this new information could help the development of therapeutics for those diseases.

It has been known that a molecule called Smoothened moves into a cellular structure called a cilium (shown in the video) and is then able to activate the smoothened pathway. Most cells in the body have a primary cilium, which acts as a sort of antenna for the cell, picking up cues from the environment and helping the cell respond to them in a variety of ways. Cells are able to secrete things, take things up, or move around, for example.

Smoothened is prevented from entering the cilium under typical conditions, which keeps the pathway under control. For this work, the scientists wanted to know how smoothened was getting into the cilium. They found that an enzyme, Phospholipase A2 gets the process going. In addition, the enzyme seems to “supercharge” the signal from the Smoothened.

"We've basically revealed a new layer of regulation of Smoothened trafficking,"  said Stacey Ogden, Ph.D., an associate member of the St. Jude Department of Cell and Molecular Biology. "This is a very hot area of research now, because Smoothened trafficking appears to be a very crucial control point for signaling activity. So, if you can change Smoothened trafficking, you can very easily adjust the amplitude of Sonic Hedgehog signaling."

Ogden explained that these findings could have a clinical impact, since a reduction in the Sonic Hedgehog pathway activity is a common feature of ciliopathies, genetic disorders relating to primary cilia like Joubert syndrome, Bardet-Biedl syndrome and one of the most common genetic disease in the US, polycystic kidney disease. 

This image shows first author Angela Arensdorf, Ph.D., and corresponding author Stacey Ogden, Ph.D., an associate member of the St. Jude Department of Cell and Molecular Biology. / Credit: Peter Barta / St. Jude Children's Research Hospital

On the other side of dysfunction, over activation of the Sonic Hedgehog pathway causes around 30 percent of childhood medulloblastomas, the most common malignant brain tumor in children. Patients are in desperate need of better treatment options; they currently have to confront a host of terrible side effects and underwhelming efficacy.

"One of the drugs now being used to treat medulloblastoma is a Smoothened inhibitor," Ogden explained. "But tumor cells frequently become resistant to this drug and begin to grow again because of mutations in Smoothened that enable it to overcome the drug's inhibition. We want to determine whether drugs to inhibit Phospholipase A2 could reduce Sonic Hedgehog activity in cases where Smoothened becomes insensitive to targeted inhibition.”

Overactivation of the Hedgehog pathway in adults causes basal cell carcinoma, a very common cancer. Hedgehog pathway activation could be encouraging other types of tumors by influencing the tissue in around the tumor, the stroma, to create an environment that promotes growth, Ogden said.

"So Hedgehog pathway inhibitors may be useful in combination therapies with other traditional chemotherapies for other types of solid tumors," she said.

Ogden and her colleagues are continuing to investigate how Smoothened is regulated, and what drugs might affect its activity. Check out her lab in the video above.

Sources: AAAS/Eurekalert! via St. Jude Children’s Research Hospital, Cell Reports

About the Author
  • Experienced research scientist and technical expert with authorships on 28 peer-reviewed publications, traveler to over 60 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
MAR 05, 2020
Microbiology
MAR 05, 2020
Researchers Learn How Gut Microbes Can Promote Heart Disease
The microbes in our gastrointestinal tract, collectively known as the gut microbiome, have a powerful impact on our heal ...
MAR 31, 2020
Microbiology
MAR 31, 2020
Researchers Suggest Repurposing Pancreatitis Drug to Treat COVID-19
As SARS-CoV-2 upends normalcy in the world, researchers are trying to find a treatment for the illness it causes.
APR 14, 2020
Cell & Molecular Biology
APR 14, 2020
Combining Methods to Learn More About Protein Interactions
Proteins usually work together, whether as part of a pathway or a complex, and there are several ways to investigate pro ...
APR 23, 2020
Cardiology
APR 23, 2020
Arteries Respond in Different Ways in Females and Males
Exploring Arterial Smooth Muscle Kv7 Potassium Channel Function using Patch Clamp Electrophysiology and Pressure Myograp ...
MAY 13, 2020
Cell & Molecular Biology
MAY 13, 2020
Combined with Fasting-Mimicking Diet, Vitamin C May Have Anti-Cancer Effect
People have long been searching for natural ways to treat cancer in an effort to avoid some of the harmful side effects ...
MAY 24, 2020
Cell & Molecular Biology
MAY 24, 2020
Common Chemicals May Contribute to Obesity
Several explanations have been proposed to answer the question of why obesity has been on the rise for many years in the ...
Loading Comments...