Proteins in human cells are decorated with different types of sugars as a result of glycosylation. These modifications affect a protein's function. New research that will be published in the Journal of Biological Chemistry on September 22, shows that a rare type of glycosylation profoundly impacts the function of a protein important for human development and cancer progression. The work comes from Robert Haltiwanger, Ph.D.'s lab at the University of Georgia.
In this new study, researchers found that there were sugars attached to the protein Notch, a signaling receptor that is essential for cell development and differentiation and is dysregulated in cancers such as leukemia, breast cancer, and prostate cancer.
The enzymes responsible for modifying Notch with glucose and fucose are called POFUT1 and POGLUT1. Haltiwanger's team, led by Hideyuki Takeuchi, Ph.D., wanted to know exactly why POFUT1 and POGLUT1 were attaching glucose and fucose to Notch in cells.
Haltiwanger's work shows that the fucose and glucose modifications serve as quality-control markers that allow Notch to be transported to its final destination in the cell membrane. When the researchers knocked out POFUT1 or POGLUT1 in cell cultures using CRISPR/Cas technology, cells displayed much less Notch on the cell surface. When both enzymes were knocked out, Notch was almost completely absent. Using additional biochemical methods, the researchers found that POFUT1 and POGLUT1 attached glucose and fucose to portions of Notch only after they fold in a specific way.
Now that the researchers know these sugars are essential for Notch activity, POFUT1 and POGLUT1, become potential targets for cancer treatments. Depending if Notch activity is too high or too low, the researchers belive that if they can to manipulate the sugars that are added to Notch, then they could help correct the dysregulation.
Currently, the scientists are working on finding chemical compounds that would inhibit POFUT1 and POGLUT1, thus stopping Notch from embedding in the cell membrane and carrying out its signaling functions. They're also attempting to unravel the details of how the glucose and fucose modifications work together to fine-tune Notch activity.