Scientists headed by ICREA researcher Marco Milán, 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 Milán, 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 Milán'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 agentIn 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.
Indeed, the analyses demonstrated that the Notch receptor sequesters the ligands and prevents these from connecting to the Notch receptors of adjoining cells. The experiments showed that the absence of the receptor in the mutated cells leaves many ligands free, ready to enter into contact with Notch receptors of the non-manipulated cells. "It is strange, but in the cell emitting the signal, Notch receptor captures the ligands by acting as a silencer while in the cell receiving the signal the binding of ligands with Notch allows activation of the pathway". "In fact", says Milán, "it is all to do with a fine balance between ligands and receptors of the emitting and receiving cell". In other words, Notch is a kind of double agent and exerts opposing functions: repressing or activating the pathway depending on whether it is located in cells emitting or receiving the signal. It must be noted that such a simple activation system involves multiple repression mechanisms, "because this is a crucial but also dangerous signalling pathway", explains Milán.
The researchers have discovered the self-repression mechanism of Notch in Drosophila and it should be checked now whether this also operates in mice and humans. They speculate that it does because the ligand-receptor system of Notch activation has been conserved in all organisms. "If this new mechanism is also present in vertebrates, it should be taken into consideration when designing effective therapies against certain kinds of cancer, such as T-cell acute lymphoblastic leukaemia (T-ALL)", concludes Milán.
It is well established that the Notch pathway controls the development of T lymphocytes, cells of the immune response system found in blood. The cells destined to become lymphocytes receive the appropriate signalling through Notch receptors. In more than half T-ALL patients the Notch receptor is permanently activated in the T-cell precursors. Thus the continuous proliferation of cells is stimulated until tumours form. "A priori, blocking the Notch receptor could appear to be a good strategy to combat this kind of leukaemia. However, the results of our work suggest that blocking the receptor only in some cells would cause undesirable effects in adjacent cells", warns Milán.
A role of Notch in ligand cis-inhibition in Drosophila. Isabelle Becam, Ulla-Maj Fiuzza, Alfonso Martínez-Arias and Marco Milán. Current Biology, 2009. doi: 10.1016/j.cub.2010.01.058
Sònia Armengou | EurekAlert!
What happens in the cell nucleus after fertilization
06.12.2016 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
06.12.2016 | Materials Sciences
06.12.2016 | Medical Engineering
06.12.2016 | Power and Electrical Engineering