His findings with animal cells are supported by studies in flies in the May 15 issue of Cell and the June 18 issue of Current Biology . Notch1 is crucial in the early development of cells such as neurons in everything from worms to humans. Researchers had known that the protein becomes activated when the part of it that juts outside of a cell serves as a receptor and binds to nearby cells. But no one had clarified how this surface interaction causes changes inside a cell. Kopan showed that a part of the receptor that hangs inside the cell is released so it can serve as a cell-fate messenger by traveling to the nucleus to influence gene activity.
Notch is thought to play a role in certain cancers when it stays activated, favoring cell division.
Mutations that result in a shortened Notch1 protein occur in certain human leukemias. Preliminary results also suggest that a Notch switch may be tripped too easily in cervical cancer or breast cancer, with the latter case involving another Notch protein thought to be similar in function to Notch1. He also is investigating a potential link between the Notch1 signaling pathway and that of early-onset Alzheimer's disease in collaboration with Alison Goate, Ph.D., associate professor of genetics and psychiatry. Kopan began his studies by isolating the inside fragment of Notch 1 that was released after the protein was activated in tissue culture cells. With this, he determined the site in the chain of amino acids where cleavage occurred.