C1 - The role of gp130-trans-signalling in liver regeneration and cancer: therapeutic perspective

C1_April 2014

Principal Investigators:

Dr. rer. nat. Dirk Schmidt-Arras
Biochemisches Institut
Christian-Albrechts-Universität zu Kiel
Olshausenstr. 40
24098 Kiel
Tel.: +49-431-880-7112
Fax: +49-431-880-5007
E-mail: darras@biochem.uni-kiel.de
Homepage

Prof. Dr. rer. nat. Stefan Rose-John
Biochemisches Institut
Christian-Albrechts-Universität zu Kiel
Olshausenstr. 40
24098 Kiel
Tel.: +49-431-880-3336
Fax: +49-431-880-5007
E-mail: rosejohn@biochem.uni-kiel.de
Homepage

C1_IL-6 trans-signaling
Figure 1: Possible involvement of IL-6 trans-signaling and ADAM proteases in the development of inflammation-related malignant liver lesions

Project description

On target cells Interleukin-6 (IL-6) binds to its membrane-bound receptor (IL-6R) and the signal-transducing subunit gp130/IL-6ST. The soluble IL-6 receptor (sIL-6R) can be liberated proteolytically mainly by the metalloprotease ADAM17. In complex with the sIL-6R, IL-6 can bind now to cells that express gp130 but not the membrane-bound IL-6R. This process has been termed IL-6 ‘trans-signaling’. IL-6 trans-signalling via gp130 has been shown to play a pivotal role in liver regeneration, but also inflammatory and tumorigenic processes. gp130 has been shown to be mutated in hepatocellular adenoma and carcinoma.

C1 in 60 SecondsVideoarchiv

online seit 11.09.2014

During the first funding period we were able to show that oncogenic mutations in gp130 lead to an increased flexibility of the gp130 extracellular domain and in consequence to ligand-independent activation. We could furthermore reveal that gp130 mutants signal from intracellular compartments.

In the future we will analyse the detailed molecular basis of gp130 activation. We will furthermore compare the spatio-temporal regulation and signal quality between ligand-stimulated and constitutive active gp130. Using cell biological approaches and animal models we will analyse the physiological consequences of persistent hepatocellular gp130 trans-signalling in vitro and in vivo.

In previous work we could identify ADAM-proteases in cells of the tumour stroma and cells of the metastatic niche as major switches for the generation of lung metastasis. Based on these findings we will analyse if ADAM proteases also play a crucial role for the generation of malignant hepatic lesions and hence present a target for therapeutic intervention.

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