Researchers unlock the secret of the Hippo-YAP pathway
The protein angiomotin has been the focus of much recent research, but confusion remains about its exact role in a critical cancer-linked pathway. Researchers from the Florida campus of The Scripps Research Institute (TSRI) have now uncovered the regulatory machinery underlying the protein that has been described a cell proliferation inhibitor and activator.
In an article published in the journal eLife, TSRI investigators found that angiomotin’s activities depend on phosphorylation—when a phosphate group is added to its structure at a specific location. If a phosphate group is added, then the protein inhibits cell proliferation. Take away a phosphate group from its normal configuration, and cancer growth is encouraged.
The study, led by Joseph Kissil, PhD, Associate Professor in the Department of Molecular Medicine at TSRI, was recently published in the journal eLife. It sheds new light on the signaling pathway in cells called the Hippo-YAP pathway.
YAP’s involvement in cancer has been demonstrated in liver, intestine, heart, pancreas, and brain tissue, and recent studies show it plays a key role in 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. However, some studies give angiomotin a YAP-inhibitory function, while others indicate that the protein is required for YAP activity.
Dr. Kissil and his colleagues discovered the source of the seemingly contradictory reports. YAP forms a complex with angiomotin and Merlin, another protein. When angiomotin is phosphorylated, it 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 Sany Hoxha, a TSRI graduate student and 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 Dr. Kissil.
The study was supported by the National Institutes of Health and the Children’s Tumor Foundation.
To read more about this study, click here.