Scientists headed by ICREA researcher Marco Mil-n, at the Institute for Research in Biomedicine (IRB Barcelona), reveal a surprising new function of Notch protein that contrasts with the one known to date. Found in the cell membrane, this protein activates a signalling pathway that regulates the expression of genes that make the cell divide, grow, migrate, specialise or die. Notch activity is required for the correct development of organisms and for the maintenance of tissues in adults. When Notch acts at an incorrect time or in an incorrect context, it can give rise to the generation of tumours, among these leukaemia, breast cancer, colon cancer, skin cancer, lung cancer and renal carcinomas.
"The same pathways responsible for the development and growth of organisms are involved in the transformation of healthy cells into cancerous ones", says Marco Mil-n, so "all new data on the modulation of Notch activity, the first step in the chain, may be relevant for the design of effective therapies". Marco Mil-n's group has now discovered that the presence of Notch proteins in the cell membrane is also required to inactivate the pathway. The description of the new role of Notch, found in the fly Drosophila melanogaster, and the mechanism that regulates this function have been published in the journal Current Biology, which belongs to the Cell group.
Stop! Notch is a double agent
In order for the Notch pathway to be activated, ligand-type proteins from neighbouring cells bind to the Notch receptor. When the ligand and receptor come into contact, the Notch receptor is processed and the intracellular part moves to the nucleus to activate gene expression. This is the basic and "extremely simple activation system" of the Notch signalling pathway, which is based on short distance contact between cells through a ligand and a receptor.
In a developing wing and through a technique called Clonal Analysis, the researchers manipulated groups of cells, among groups of normal cells, to remove Notch receptor expression. The scientists used the Drosophila wing because it is an excellent model to describe how cells behave when a certain gene is mutated and to determine and test how this mutation affects adjacent cells. This was the objective of the study designed by Isabelle Becam, post-doctoral researcher in Mil-n's Group and first author of the article. "As expected, the cells lacking Notch did not activate the pathway, but what was surprising was the observation that neighbouring cells did". Becam then questioned whether the absence of Notch in a group of mutated cells could cause activation.