The Notch signalling pathway is one of the major signalling pathways involved in the development of living organisms. Its regulation is essential to ensure that every individual is born with “everything as and where it should be”. In collaboration with researchers from the Goethe University in Frankfurt, Franck Dequiedt has revealed a new control mechanism in the Notch signalling pathway.  

By definition, an organism is a collection of elements composing a functional structure. In biology, an organism refers to all the cells, tissues and organs that comprise an individual. It is the interaction between these multiple elements, but also the adaptation of these elements to external stimuli, that enable organisms to live and survive. Although highly complex and still far from being fully known and understood, the development of higher organisms relies on several important signalling pathways. Theses pathways consist of a series of molecular events triggered by a stimulus and enabling the transmission of a signal within a cell or from one cell to another. Of particular importance among theses pathways is the Notch cascade.

“It is pathways such as Notch, Homeobox or Wnt that determine into which animal an organism is going to develop. They play many different roles and are involved in organogenesis during several stages of development”, explains Franck Dequiedt, a "research associate" of the FNRS at the Faculty of Agro-Bio Tech in Gembloux and GIGA at ULg. But how are just a few signalling pathways at the origin of the great diversity of organisms that exist on earth? “For such biodiversity to be possible, these pathways must be flexible and adaptative to the vairations of the environment”, continues Franck Dequiedt. Hence the interest in understanding how these pathways are modulated and controlled.

Ubiquitin, not the only commander on board

Over the past few years, there has been a new boom in research on the Notch signalling pathway. Scientists have discovered that this pathway is involved in the specification of stem cells; in addition, a deregulation in this pathway can lead to the appearance of cancer. In brief, the Notch pathway functions as follows: Notch is a transmembrane receptor that is activated by two major families of ligands. These ligands bind to the extracellular part of the Notch receptor, thus causing a portion in the intracellular part of the receptor to be cleaved off. This part, known as the NICD (Notch intracellular domain), migrates from the cytoplasm to the nucleus, where it activates the expression of the genes involved developmental programs.

During its migration from the membrane to the cell nucleus, the stability of NICD  is tightly controlled, i.e. the cell may or may not degrade it. “This protein can be marked by another protein, ubiquitin, which indicates to a proteasome, a cellular machinery specialized in degradation of proteins, to degrade the NICD by proteolysis. This allows the cell to control the intensity and the duration of the Notch signal”, Franck Dequiedt points out.