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 transmission depends on the spatial organization of the cell as well as the number of individual proteins involved. The number of molecules differs between a few dozens scaffolding proteins and thousands for the final MAP kinase, which is responsible for transducing the signal from the membrane bound protein complexes towards the cell’s nucleus. Abnormal regulation of MAPK cascades contributes to cancer. This project aims to better understand the influence that the spatial organization of a cell has on the organization of protein complexes and thus the efficacy of cell signaling. Therefore, we develop a spatio-temporal agent-based model for protein complex formation and cell signalling. Simulation results will be compared to an available comprehensive dataset for breast cancer, comprising of time-resolved transcriptomic, (phosphor-)proteomic and imaging data.
The model will incorporate protein diffusion in two and three dimensions, describing membrane-bound and cytosolic movement of proteins respectively. Spatial restriction caused by intracellular organelles, which may limit the accessibility of protein (or shield the protein), are considered. By tracking the interactions of each protein, the underlying protein network can be extracted and analyzed.
A): Real cell microscopic image, B) Complex formation around EGF receptor, C) Schematic of cell with signaling proteins, D) Network graph representing the agent flow within a cell between neighboring subdomains (regions of interest). Reactions of agents are considered as processes on the nodes. Spatial movement of agents is allowed to neighboring subdomains and considered as flows from each node to their neighboring nodes connected by edges.