Molecular mechanisms of Notch signal 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 cooperation with director Cheon Jin-woo of the Center for Nanomedicine Research (Professor of the 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) announced on the 10th that they have identified the process of activating receptor signals and the mechanism by which amyloid is formed the beta protein (Aβ), known as the cause of Alzheimer’s. 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-cell interaction regulating 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 the sequential cleavage of Notch receptor and amyloid precursor protein by two types of enzymes present in the cell membrane. Identifying the 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 the junctions between cells, act as a switch that determines the sequence of sequential cleavage processes and are essential for normal Notch signaling 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 joint structure.
Prior to 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 begins to activate, is cleaved by the ADAM enzyme from outside the adhesive junction structure, and the smaller receptor approaches inside the adhesive junction. Notch receptors that have entered the adhesive junction undergo a second cleavage process by the enzyme γ-secretase recruited at high concentrations within it, leading to the activation of signal transduction.
Using ‘mechanogenetics’, a nanotechnology capable of delivering mechanical and spatiotemporal stimuli to specific receptors, the researchers discovered that adhesive junctions recruit gamma secretase enzymes in high concentrations and block access to Notch receptors that have not undergone the first process of cleavage.
It turned out that the Notch signal was not activated when the expression of the protein cadherin was knocked out by current gene-editing technology. When cadherin expression was suppressed in developing mouse brain neural stem cells, the stem cells differentiated into neurons abnormally rapidly. This demonstrates that the process of Notch signal control 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. He showed that the formation of amyloid-beta, known as the main cause of Alzheimer’s disease, can be inhibited by controlling the protein cleavage process.
Professor Jeon Young-wook said: ‘For the first time, we have presented the molecular and cellular mechanisms of the sequential cleavage process of proteins required for Notch signaling activation and beta-amyloid formation.’
Professor Min-seok Kwak said: ‘We expect to contribute to cancer research through abnormal cell signaling and Alzheimer’s disease treatment research through inhibition of beta-amyloid formation.’
