How cells communicate to activate Notch
Essential research for design of potential therapeutics for numerous Notch-related diseases, in particular cancer
- Date : 11 Jun 2012
- Topic : Personalised medicine
During formation of multi-cellular organisms, cells need to talk to each other to make critical decisions as to what kind of cell to become, as well as when and where to become that cell type. The Notch signalling system allows cells to directly talk to each other to programme almost every cell type in the body. Now, researchers have shown for the first time that the mechanical force produced by cell-cell interactions is critical for programming by the Notch signalling system.
Prior to these findings, it was speculated that interacting cells undergoing Notch signalling pull on each other to unlock and activate Notch. Now, the UCLA's Jonsson Comprehensive Cancer Centre scientists detail how the process unfolds, a discovery that could result in potential new targets for therapeutics, according to Gerry Weinmaster, a professor of biological chemistry and co-senior author of the studies, who has been studying Notch signalling for more than 20 years.
The findings are outlined in two companion papers that appear May 31, 2012 in the early online edition of the peer-reviewed journal, Developmental Cell.
Researchers show for the first time that the mechanical force produced by cell-cell interactions is critical for programming by the Notch signalling system
The findings used optical tweezers as a novel tool to detect and measure mechanical force produced by cells when bound to Notch. Together with biochemical and cell biological analyses, these findings provide compelling evidence that pulling on Notch opens a network to deliver information that instructs specific cellular responses.
In its normal state, Notch is folded in an inactive form that protects its proteolytic cleavage, or cutting site, that once exposed, activates signalling in cells. Weinmaster likened the unfolding and activation of Notch by mechanical force to the force required to pull a pin from a grenade to produce an explosion. One of the interacting cells, known as the ligand cell, uses mechanical force to pull the "pin" from the Notch grenade present on the other interacting cell, and this results in an explosion of sorts that sets off cellular programming by Notch.
The research team wanted to obtain evidence that ligand cells actually produce pulling force following interactions with Notch cells and contacted Elliot Botvinick, an assistant professor in biomedical engineering at the University of California, Irvine, who is an expert in optical tweezers, a scientific instrument that uses a highly focused laser beam to detect and measure mechanical forces.
To detect the pulling force, he recommended replacing the Notch cell with a Notch bead that could be laser trapped and held just-in-contact with the ligand cell. If the cell produced mechanical force, it would displace the bead from the trap, allowing the exact magnitude of the pulling force to be measured.
Botvinick determined that ligand cells could physically pull a Notch-bead from the centre of the trap. The studies also shed light on a new role for endocytosis to activate signalling in cells that is unique to Notch. These studies provide compelling evidence that ligand endocytosis produces force to pull on Notch and identifies a new role for endocytosis in activation of a signalling system.
Going forward, the team will use cutting-edge biophysical approaches to clearly understand how pulling force is used to activate Notch both in human development and disease. This research is essential for the design of potential therapeutics for numerous Notch-related diseases, in particular cancer.
The researchers conclude that the primary role of ligand endocytosis is to generate mechanical force to activate Notch signalling. Future studies to quantify the force required to dissociate Notch, as well as directly demonstrate mechanical force applied to Notch activates signalling, will extend findings and further test the pulling-force model.
These studies were funded by the University of California Cancer Research Coordinating Committee and USA National Institute of General Medical Sciences in the National Institutes of Health (RO1 GM0850232), Jonsson Cancer Centre Foundation and the Canadian Institute of Health Research, the USA National Science Foundation (DMR 0805164) and the USA National Institutes of Health (P41RR001192 and P41EB015890).
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