Mathias Müller, DVM
Department of Biomedical Sciences
The focus of our laboratory is on the Jak-Stat signaling pathway and its direct or indirect interconnection with the host response to infection, inflammation and carcinogenesis. A total of four Janus kinases (JAK1-3, TYK2) and seven STATs (STAT1-4, STAT5A, STAT5B, STAT6) act in various combinations to stimulate appropriate nuclear responses to cytokines and growth factors. Upon ligand binding, receptor-associated JAKs phosphorylate recruited STATs thereby initiating nuclear translocation and DNA binding. This linear pathway constitutes the canonical JAK-STAT signaling. JAKs also initiate non-STAT signaling pathways and show kinase- independent functions. In addition to phosphorylation, STATs exert biological activity through additional or alternative modifications. JAKs and STATs also show non-receptor associated functions. These activities are summarized as non-canonical. We employ mouse reverse genetics, genome editing and comparative biomedicine to study signaling involved in immunity to infection, inflammation and carcinogenesis as well as the consequences of non-canonical JAK-STAT activities. The molecular focus on the TYK2-STAT1/3 axis. For these molecules the lab has generated a comprehensive collection of mutant mice enabling to study loss of function, tissue-specificity and non-canonical functions. Our lab is dedicated to translational research and comparative medicine.
The Vetmeduni Vienna – with a central role of our laboratory – is host of a special research program employing cutting edge next generation sequencing technologies studying principles that underlie switches in transcription directed by the chromatin landscape and 3D structure, such as those that occur in normal and aberrant development, in the reaction to infection and in carcinogenesis. Consortium members provide additional expertise in areas such as epigenetics, pharmacogenomics, bioinformatics and computational medicine. The consortium’s mission is to pave the way for novel therapeutic possibilities, especially with regard to personalized medicine.
Majoros, A., Platanitis, E., Szappanos, D., Cheoan, H.J., Vogl, C., Shukla, P., Stark, G.R., Sexl, V., Schreiber, R.D., Schindler, C., Müller, M., and Decker, T. (2016). Response to interferons and antibacterial innate immunity in absence of tyrosine-phosphorylated STAT1. EMBO Rep 17, 367-382. doi: 10.15252/embr.201540726.
Hainzl, E., Stockinger, S., Rauch, I., Heider, S., Berry, D., Lassnig, C., Schwab, C., Rosebrock, F., Milinovich, G., Schlederer, M., Wagner, M., Schleper, C., Loy, A., Urich, T., Kenner, L., Han, X., Decker, T., Strobl, B., and Müller, M. (2015). Intestinal epithelial cell tyrosine kinase 2 transduces interleukin-22 signals to protect from acute colitis. J Immunol 195, 5011-5024. doi: 10.4049/jimmunol.1402565
Prchal-Murphy, M., Witalisz-Siepracka, A., Bednarik, K.T., Putz, E.M., Gotthardt, D., Meissl, K., Sexl, V., Müller, M., and Strobl, B. (2015). In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity. Oncoimmunology 4, e1047579. doi: 10.1080/2162402X.2015.1047579
Strobl, B., Stoiber, D., Sexl, V., and Müller, M. (2011). Tyrosine kinase 2 (Tyk2) in cytokine signalling and host immunity. Front Biosci 16, 3224-3232. [review] doi: 10.2741/3908
Vogl, C., Flatt, T., Fuhrmann, B., Hofmann, E., Wallner, B., Stiefvater, R., Kovarik, P., Strobl, B., and Müller, M. (2010). Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genes. BMC Genomics 11, 199. doi: 10.1186/1471-2164-11-199