The signal transduction network processes extra- and intracellular stimuli and transmits them to the nucleus where the genetic programme of the cell is controlled. How do these signalling pathways process the information and control gene expression in a reliable way? We have recently analysed gene-expression patterns after pathway activation for the five major signalling systems in Mammals (1), and found that all pathways are regulated in the same manner: Upon pathway activation, short-lived inhibitory proteins are expressed such as phosphatases. Using mathematical modelling I could show that such a feedback design is a perfect design to overcome two major challenges in mammalian signal transduction: First, it allows for rapid induction of target proteins, and, second, it reduces the noise in the expression of target genes (2). By using a combination of bioinformatics, model-selection and targeted experimentation we recently identified one such feedback involving the phosphatase DUSP6 that is important when cells transform into cancer cells (3).

It becomes more and more clear, that at least MAPK signalling is not only controlled by one negative feedback, but by a phalanx of feedback loops mainly mediated by the DUSP phosphatases. It is believed that this feedback system is partially responsible for oncogene addiction and failure of the MEK inhibitor in the cure of cancer. The complexity of this network is such that one can no longer predict the dynamics of the system (4). However, sufficient experimental tools are available to measure and perturb the system such that data can be generated to parametrise a mathematical model for it. We are therefore building and analysing a model of this complex feed-forward and feedback-loop system. Moreover, it seems that these negative regulators also mediate crosstalk between signalling pathways, giving potentially rise to a more specific response. Such crosstalk exists for example between the WNT and the MAPK pathway. We combine experimental end theoretical approaches to the system and collaborate with the following experimental groups: C. Sers (Berlin), R. Schäfer (Berlin), M. Schwarz (Tubingen) and P. Lenormand (Nice, France).

1. Legewie S, Herzel H, Westerhoff HV, Blüthgen N: Recurrent design patterns in the feedback regulation of the mammalian signalling network. Molecular Systems Biology 2008 4:190
2. Blüthgen N: Why do signal transduction cascades induce their own inhibitors? submitted
3. Blüthgen N, Legewie S, Kielbasa SM, Schramme A, Tschernitsa O, Keil J, Vingron M, Schüfer R, Herzel H, Sers C: A systems biological approach unveils a transcriptional feedback loop shaping ERK activity in RAS-transforming fibroblasts, submitted.
4. Blüthgen N, Legewie S: Systems analysis of MAPK signal transduction. Essays in Biochemistry 2008, in press