JUL 11, 2017 1:42 PM PDT

Scientists Solve Major Cancer Protein Conundrum

Despite intense research, there’s been much confusion regarding the exact role of a protein in a critical cancer-linked pathway. On one hand, the protein is described as a cell proliferation inhibitor, on the other, a cell proliferation activator, a duality that has caused a great deal of scientific head scratching.

Now scientists from the Florida campus of The Scripps Research Institute (TSRI) have solved the conundrum, uncovering the regulatory machinery underlying the function of a protein, called angiomotin.

The researchers found that angiomotin’s activities depend on a process called phosphorylation—when a phosphate group is added to its structure at a specific location. Add a phosphate group, and the protein can inhibit cell proliferation. But remove a phosphate group from its normal makeup, and the protein promotes cell proliferation, encouraging cancer cell growth.

The study, led by Joseph Kissil, associate professor in the Department of Molecular Medicine at TSRI, was recently published in the journal eLife.

Protein’s Position in Cells is Key

The new study sheds light on signaling pathway in cells called the Hippo-YAP pathway.

YAP’s involvement in cancer has been demonstrated in several tissues, including liver, intestine, heart, pancreas and brain. Recent studies show YAP plays a key role in developing drug resistance in lung and colon cancer cells and promoting cancer in some colon and pancreatic cancers. Hippo regulates cell proliferation and programmed cell death, which often become corrupted in diseases like cancer.

Whether the Hippo-YAP pathway can be altered by the protein angiomotin is not in question. But while some studies give angiomotin a YAP-inhibitory function, others indicate that the protein is required for YAP activity.

Kissil and his colleagues discovered what lies at the heart of those seemingly contradictory reports. They found that YAP forms a complex with angiomotin and another protein called Merlin. When angiomotin is phosphorylated, that changes the localization of this complex to the cell plasma membrane where it prevents cells from proliferating.

“The relocation of the protein complex out of the nucleus to the plasma membrane prevents YAP from operating as a growth-promoting transcriptional activator,” explained TSRI Graduate Student Sany Hoxha, co-first author of the study.

Conversely, when angiomotin is less than fully phosphorylated, the complex is localized in the nucleus, where it promotes YAP-dependent cell proliferation.

“Since this is a major pathway for diseases like cancer and fibrosis, our findings add a brand-new layer of valuable information,” said Kissil.

In addition to Kissil and Hoxha, the other first author of the study, “Regulation of Localization and Function of the Transcriptional Co-Activator YAP by Angiomotin,” is Susana Moleirinho. Other authors include Vinay Mandati, Graziella Curtale and Scott Troutman of TSRI; and Ursula Ehmer of Technische Universität München, Munich, Germany.

The study was supported by the National Institutes of Health (grants NS077952 and CA124495) and the Children’s Tumor Foundation.

This article was originally published on scripps.edu

About the Author
  • The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 2,700 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists-including two Nobel laureates-work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
You May Also Like
DEC 14, 2020
Genetics & Genomics
tRNA Plays a Role in the Immune Response to Stroke
DEC 14, 2020
tRNA Plays a Role in the Immune Response to Stroke
At one time, researchers knew that various forms of RNA served a few different critical roles in the creation of protein ...
DEC 17, 2020
Immunology
A Peanut a Day Keeps Allergies Away
DEC 17, 2020
A Peanut a Day Keeps Allergies Away
Canadian researchers have made a breakthrough for children with peanut allergies: immunotherapy that when taken daily fo ...
DEC 25, 2020
Immunology
A High-Fat Diet Starves Immune Cells, Tumor Growth Goes Unchecked
DEC 25, 2020
A High-Fat Diet Starves Immune Cells, Tumor Growth Goes Unchecked
  Sitting down to enjoy an indulgent Christmas feast? A recent study in mice by Harvard Medicine scientists found t ...
JAN 01, 2021
Microbiology
A New Type of Antibiotics Help the Immune System Fight Pathogens
JAN 01, 2021
A New Type of Antibiotics Help the Immune System Fight Pathogens
Reporting in Nature, scientists have identified a new group of compounds that may help us get out of the antibiotic-resi ...
JAN 03, 2021
Microbiology
Flu Season is Off to a Very Slow Start
JAN 03, 2021
Flu Season is Off to a Very Slow Start
The flu season would have typically been well underway by mid-December in a normal year. But this year, there are few ca ...
JAN 03, 2021
Cannabis Sciences
Cannabis Users Don't Understand Health Risks of Smoking, Study Finds
JAN 03, 2021
Cannabis Users Don't Understand Health Risks of Smoking, Study Finds
A recent study has found that cannabis users often classify themselves as 'non-smokers' even though they smoke c ...
Loading Comments...