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Research

Cytokines (e.g. Interleukin-6, IL-6) are mediators of the immune system, which are secreted due to infection or injury. They regulate the differentiation and activation of naive immune cells, as well as the development of an inflammation which is hallmarked by the hepatic expression of acute-phase proteins, fever and pain. Thereby cytokines contribute to the reconstitution of homeostasis in the body. However, hyperactivity of pro-inflammatory cytokines or a reduced response to anti-inflammatory cytokines contributes to a huge number of chronic diseases (e.g. allergy, rheumatoid arthritis, cancer or autoimmunity).

Cytokines bind to membrane-bound receptors to activate intracellular signalling cascades. These signalling cascades result in the activation of transcription factors that bind to specific DNA sequences (promoter) in the nucleus. Activated promoters induce the transcription of target genes, e.g. the expression of acute-phase genes in the liver. The sequential activation of signalling molecules in a signalling network enables signal enhancement, complex regulation as well as the integration of different inputs and signalling cascades.

IL-6 is a central mediator of inflammatory and developmental processes in the body. It is a major inducer of acute-phase protein synthesis in the liver, regulates the differentiation of B- and T-cells and effects migration of T-cells and monocytes. Furthermore, it is an important mediator of neuronal survival and differentiation.

IL-6-induced signal transduction is activated by binding of IL-6 to the IL-6 receptor complex consisting of the IL-6 receptor α (IL-6Rα) and the signal transducing receptor subunit gp130. After binding of IL-6, receptor associated Janus kinases (JAK1, JAK2, TYK2) are activated. Activated JAKs phosphorylate tyrosine residues in the cytoplasmic part of gp130. These phosphorylated tyrosine residues serve as binding motifs for molecules that facilitate the activation of JAK/STAT (signal transducer and activator of transcription) signalling, PI3 kinase (phosphoinositide 3-kinase) and MAP (mitogen activated protein) kinase cascades. Central elements of these pathways are the activation respectively inactivation of proteins by posttranslational modifications, conformational changes or altered cellular localisation. Molecules of special interests are so called multi-site docking proteins (e.g. Gab1). Activated multi-site docking proteins act as a cellular platform to recruit a plethora of different signalling and regulatory molecules. Along with multi-site docking proteins regulatory proteins play a central function in signal transduction. Regulatory proteins prevent a hyper-activation of signalling at physiological conditions. Important regulatory proteins in IL-6-induced signalling are protein tyrosine phosphatases (e.g. SHP2) and kinase inhibitors (e.g. the feedback-inhibitor SOCS3).

At the Department of  Systems Biology we are interested in the following topics: 

At the Department of Systems Biology we are interested in the following questions:

  • How does the multi-site docking protein Gab1 contribute to the activation of the MAPK cascade?
  • How are the MAPK, PI3K and JAK/STAT signalling pathways integrated?
  • How does IL-6 signalling interact with signalling induced by other stimuli (i.e. glucocorticoids or interleukin-1)?
  • How are the expression and activation of SOCS3 and SHP2 regulated?
  • How does the activation of a single signalling pathway result in different physiological outcomes?
  • How do disease-associated mutants of signalling components influence IL-6-induced signalling?
  • How to design new therapeutic intervention strategies based on our research results?

To answer these questions we collaborate with colleagues from systems theory located at the Universities of Magdeburg and Bochum and the Max Planck Institute in Magdeburg and national as well as international colleagues with a biological or clinical background.

Regulation of signal tranduction by the multi-site docking protein Gab1

Gab cartoon

 

JAK2 V617F-activated signal transduction (E:Bio JAK-Sys)

Gab JAKVF

Regulation of signal transduction by the proteintyrosine phosphatase SHP2

STAT MAPK Balance

Biomodel Kit - Development of a Petri Net-based model of IL-6-induced signalling

PetriNetz

Crosstalk between IL-6 and glucocorticoids

REDD1 cartoon

Quantitative modelling of interleukin-6 classical and trans-signalling (E:Bio InTraSig)

cis trans signalling

Last Modification: 04.12.2018 - Contact Person: Prof. Dr. Fred Schaper