Fudan University reveals the molecular mechanisms by which protein phase change regulates the fate of cells to determine factor positioning

polarity plays an important role in cell differentiation, development and function, and its destruction is closely related to tumor generation and metastasis. The commonality of cell polarity is that some polar protein complexes are specifically recruited to the specified membrane region and significant local aggregation occurs, but the specific mechanism has not been clarified. On February 21st, the journal
published a research paper online by Wen Wenyu, a researcher at Fudan University's Institute of Biomedical Research, entitled "Phase change of the Numb/Pon complex regulates its bottom aggregation when the fruit fly neural stem cells are asymmetrically divided." The paper reports that phase changes in proteins regulate the polarity aggregation of cell fate factors, which in turn leads to neural stem cell differentiation.
In the event of asymmetric division of fruit fly neural stem cells (NBs), fate factors and their bridging protein complexes ,such as the Numb/Pon complex, form a new moon-like aggregate in the subsome, which is then asymmetrically isolated into the bottom subcells and causes them to differentiate to produce nerve cells. The new moon aggregates occur only during the division phase, when the proteins are evenly distributed throughout the mass membrane or cytosome.
researchers found that Numb's PTB domain identifies repeated modal sequences in Pon in an atypical pattern specificity, a multi-point combination that induces liquid-liquid phase transition (LIQUID phase transition) separation of the complex, which can be spontaneously assembled in the body and in cells to form dense membrane-free liquid phase structures. This phase change droplet can be destroyed and assembled by numb PTB's competing peptides. In these phased droplets, the Numb/Pon complex is highly concentrated, but at the same time there is a rapid dynamic exchange with low concentrations of Numb/Pon proteins in the surrounding solution, a phenomenon that is highly consistent with in-body data.
researchers further demonstrated that Pon acted upstream of the Numb-Notch signaling path to promote NB differentiation, and that interference with the Numb/Pon complex phase change process would disrupt Numb's bottom positioning process during asymmetric division of fruit fly neural stem cells and affect its asymmetric separation and inhibition of the Notch signal path, resulting in tumor-like NB growth.
experts say the study not only reveals the molecular mechanism by which the Numb/Pon complex regulates asymmetric division of neural stem cells, but also suggests that phase change may be widely used in cell polarization processes, i.e. phase change caused by this protein interaction may be a common mechanism for regulating heterogeneous concentration of polar protein complexes in specific membrane regions, which also provides a new perspective on understanding the mechanism of tumor occurrence and metastasis.
It is understood that Fudan University phD students Shan Zelin and Tu Yuxuan, as well as the National University of Singapore Yeing Yang as co-authors of the paper, Fudan University Biomedical Research Institute researcher, Fudan University affiliated Huashan Hospital adjunct professor Wen Wenyu and Singapore National University Temasek Institute of Life Sciences Professor Yu Cai as co-authors of the paper. The study was also supported by Professor Zhang Mingjie of the Hong Kong University of Science and Technology, Professor Long Gafu of Nankai University, and funded by the National Major Scientific Research Program and the National Natural Science Foundation. (Source: Science Network Huang Xin)