Edda Klipp, Rune Linding, Caren Tischendorf
01.01.2022 − 31.12.2023
Within the cell, a spatio-temporal network of protein interactions is responsible for signal transduction. The rate of signal transmission depends on the spatial organization of the cell as well as the number of individual proteins involved. The high number of signalling proteins and their respective phosphorylation states requires a rule-based modeling approach to assess their dynamics. We developed such a model for protein complex formation and cell signalling in breast cancer cells, which commit to migration during a wound healing assay. To study the decision mechanism behind the commencing migration a comprehensive dataset was aquired, including imaging, proteomics, phosphoproteomic, and transcriptomic data. During migration cells change their shape as well as their phosphoproteome. To integrate these findings, we developed a spatio-temporal rule-based model for cell signalling.
The current model describes the initial steps of the well-studied RAS-RAF-MEK-ERK pathway and it incorporates protein diffusion in two and three dimensions, describing membrane-bound and cytosolic movement of proteins, respectively. The cell shape in the model is currently assumed to be spherical/ellipsoidal, but will be later replaced by more realistic shapes extracted from the imaging data. Furthermore, the phosphoproteomics data will be used to identify sub-networks which show changes during the migration process. Those sub-networks can then be simulated in realistic cell shapes to study the influence of the shape on the signal transduction in silico.
When MDA-MB231 cells migrate, they change shape and phosphoproteome. To integrate these findings a spatio-temporal, rule-based model is developed.