Molecular mechanisms of Notch signaling activation. Provided by IBS
Scientists have discovered how proteins that cause cancer and Alzheimer’s are formed using nanotechnology.
The Institute for Basic Science (IBS) is a notch that plays an important role in tissue development using nanotechnology and cell engineering technology in collaboration with Director Cheon Jin-woo of the Center for Nanomedicine Research (Professor of Department of Chemistry, Yonsei University), Professor Min-seok Kwak of Yonsei University School of Advanced Sciences, and Professor Young-wook Jeon of California State University (UCSF). (Notch) announced on the 10th that they have identified the process of activating receptor signals and the mechanism by which amyloid beta (Aβ) protein, known as the cause of Alzheimer’s, is formed. The research results were published on December 2 last year in the international journal Nature Cell Biology.
Notch signaling is known to be an important cell-to-cell interaction that regulates cell division and neuronal development. Faulty Notch signaling is a direct cause of various diseases, especially cancer. In addition, amyloid beta, which is formed from amyloid precursor protein (APP), accumulates in tissues, causes nerve damage, and is involved in the development of Alzheimer’s disease.
Interestingly, both Notch activation and amyloid beta formation occur through sequential cleavage of the Notch receptor and amyloid precursor protein by two types of enzymes present in the cell membrane. Identification of factors in the amputation process and understanding the control principles are very important for understanding essential life phenomena such as stem cell and tissue development, as well as for preventing and treating diseases such as cancer and Alzheimer’s.
The research team found that adhesive synapses, which are structures that control junctions between cells, act as a switch that determines the sequence of sequential cleavage processes and are essential for normal Notch signal control. In particular, they found that the interaction between the Notch receptor and its ligand (a substance that binds to the receptor and regulates its activity) and the first cleavage process of the receptor occurs outside the adhesive junction structure, and the second cleavage process occurs within the adhesive junction structure.
Before activation, the size of the Notch receptor is greater than the width of the adhesive junction, limiting access to the adhesive junction. The Notch receptor, which binds to the ligand and starts to activate, is cleaved by the ADAM enzyme from the outside of the adhesive junction structure, and the smaller receptor approaches the inside of the adhesive junction. Notch receptors that have entered the adhesive junction undergo a second cleavage process by the γ-secretase enzyme recruited at high concentrations therein, leading to activation of signal transduction.
Using ‘mechanogenetics’, a nanotechnology that can deliver mechanical, spatiotemporal stimuli to specific receptors, the researchers found that adhesive junctions recruit gamma secretase enzymes at high concentrations and block access to Notch receptors that have not undergone the first cleavage process. I checked.
It was found that the Notch signal was not activated when the expression of the cadherin protein was eliminated by the actual gene editing technology. When cadherin expression was suppressed in developing mouse brain neural stem cells, the stem cells differentiated into neurons abnormally quickly. This proves that the process of controlling the Notch signal by adhesive junctions is involved in the development of the nervous system.
They also found that the amount of amyloid beta formed was reduced when the formation of adhesive junctions was inhibited in cells expressing the amyloid precursor protein. It showed that the formation of amyloid beta, known as the main cause of Alzheimer’s, can be inhibited by controlling the protein cleavage process.
Professor Jeon Young-wook said, “For the first time, we have presented the molecular and cytological mechanism of the sequential cleavage process of proteins required for Notch signal activation and amyloid beta formation.”
Professor Kwak Min-seok said, “We expect to contribute to cancer-related research by abnormal cell signaling and research on Alzheimer’s disease treatment through inhibition of amyloid beta formation.”