Modelling mammalian signal transduction pathways:
IKK/ NF-κB signalling and Wnt/ β-catenin signalling
In a collaborative approach with the group of Claus Scheidereit at the MDC we aim for a systems level understanding of the IKK/ NF-κB signalling pathway. This pathway consists of a canonical and a non-canonical branch. Both have a distinct timing and distinct biological functions but are interconnected. On the one hand substrates and inducers of the non-canonical branch are produced in the canonical branch, on the other hand a control of the canonical part by the non-canonical branch was reported. We are interested in the regulation of the long-time behaviour of the overall pathway and its malfunction in diseases. In particular, we want to dissect the contribution of canonical and non-canonical modules under these conditions. To that end we are investigating the kinetic properties, feedback regulations and interacting modules of both signalling branches.
The Wnt/ β-catenin pathway is another important signal transduction pathway. Its deregulation is associated with various types of cancer. We use mathematical modelling of the canonical Wnt/ β-catenin pathway to analyse the effect of transcriptional feedbacks (e.g. via Axin, β-TrCP/ HOS) and the cross-talk of Wnt/ β-catenin signalling to other pathways, most importantly NF-κB.
Quantification of mammalian gene expression
In a collaborative project with the groups of Matthias Selbach and Wei Chen (both MDC) the multistep process of gene expression including transcription, translations and the turnover of mRNA and protein was for the first time quantified on a genome-wide scale. Our approach, combining mass-spec measurements, next generation sequencing and mathematical modelling, comprised the simultaneous measurement of absolute mRNA and protein abundance and turnover by parallel metabolic pulse labelling. The synthesis rates of mRNAs and proteins were predicted by mathematical modelling. An important finding is that the cellular abundance of proteins is predominantly controlled at the level of translation. The study also shows that genes with similar combinations of mRNA and protein stability share functional properties.
Metabolic synchronisation by travelling waves in cell layers
Fig. Simulation of travelling waves in a yeast cell layer. Local addition of glucose leads to a repetitive formation of metabolic wave fronts with a constant period. The waves annihilate upon head-on collision. (a) Distribution of intracellular substrate shortly before and after the collision of wave fronts, (b) corresponding time-space-plot.
The coordination of cellular dynamics is a prerequisite of the functionality of tissues and organs. Generally, this coordination may occur by signal transduction, neuronal control, or exchange of messenger molecules. The extent to which metabolic processes are involved is less understood. Previously, a communication between cells via the exchange of metabolites, called dynamic quorum sensing, was shown in stirred cell suspensions. However, it was an open question whether the coupling of cells without stirring would be sufficient for the coordination of cellular behavior. We studied this question by an experimental-theoretical approach using a simple experimental system, that is, a layer of resting yeast cells. We could for the first time show that a local addition of substrate led to the formation of intercellular glycolytic waves in these cell layers. The theoretical analysis of this phenomenon showed that the radial wave velocity arises from the substrate gradient. Overall, the results demonstrate that metabolic processes introduce an additional level of local intercellular coordination.