Mathematical modeling of TNFR1 signaling 


Death receptors such as TNFR1 (tumor necrosis factor receptor 1) control essential cellular processes like proliferation, inflammation, and cell death. Thus, it features a strict regulatory network to modulate the cellular response following death receptor engagement. Nevertheless, these pathways are often found to be disrupted in cancer cells and other inflammatory diseases. To elucidate these intertwined cellular pathways and their molecular regulation, we apply systems biology approaches.
The project addresses in particular the assembly and activity of macromolecular complexes regulating cell death. We focus on the induction of NF-?B pathway, apoptosis and necroptosis by activation of TNFR1, emphasizing the regulatory role of post-translational modifications (different types of ubiquitination and phosphorylation). Based on data of our collaborators, we model this signaling network mathematically applying Petri net formalism (semi-quantitative, stochastic, ordinary differential equation (ODE)-based). The mathematical model delivers a valuable tool for investigating the regulatory mechanisms on a basic molecular level. This may allow us to identify potential fragile parts of the signaling pathway as crucial points to perturb this system.

Figure 1: Scheme of TNFR1 signal transduction. Fallowing TNFa engagement, the receptor signaling complex (RSC) associates. The RSC consists of adaptor proteins, RIP1 as well as E3 ubiquitin ligases. These ligases generate different linkage types of ubiquitin chains on RIP1 to attach kinases to the RSC, which can activate the transcription factor NF-?B. Thus, the transcription factor can induce the expression of target genes that facilitate cell survival and regulate TNFR1 signaling. Another cytosolic signaling complex II (SCII) can be formed composed of additional adaptor proteins and caspase 8, which can activate the caspase cascade and results in cellular apoptosis. If caspases are absent or inhibited, the kinase RIP3 associates to the complex and initiates necroptosis via crossphosphorylation with RIP1.

Project members

This project is part of the 'Cluster of Excellence Frankfurt Macromolecular Complexes' www.cef-mc.de in collaboration with the groups of

Ivan Dikic

Volker Dötsch

Simone Fulda

Mike Heilemann

In our group, Molecular Bioinformatics, Ina Koch, Jennifer Scheidel and Leonie Amstein work on the project.

Posters:

Mathematical Modelling of the Function of Ubiquitylation in TNFR1-Mediated NF-?B Signalling. CSMB 2013, Wien
Modeling NF-?B signal transduction using Petri nets. Molecular life science 2013, Frankfurt am Main
Mathematical model of TNFR1 signal transduction. GCB 2014, Bielefeld