A 6: Posttranslational modification of the insulin signal transduction pathway in vivo
Prof. Dr. Jens Brüning
Institut für Genetik, Universität zu Köln
email: jens.bruening@uni-koeln.de
phone: +49-(0)221 470 2467?
website
Insulin receptor substrate (IRS)-proteins play a pivotal role in control of glucose homeostasis and their posttranslational modifications during the development of obesity have been shown to cause insulin resistance and subsequent occurrence of type 2 diabetes mellitus. To detect alterations in insulin-stimulated protein complex formation under conditions of obesity in vivo, we have generated tandem affinity purification (TAP)-tagged knock-in mice for the major insulin receptor substrate proteins IRS-1 and IRS-2. In the previous funding period we have performed affinity purifications of IRS-1 and associated proteins from liver of lean mice compared to obese mice due to high fat feeding. Label-free, mass spectrometry-based quantification of IRS-1-associated proteins in liver revealed the successful detection of previously described IRS interacting partners in vivo. Moreover, insulin-stimulated IRS-1 association with 14-3-3 epsilon was reduced in liver of obese animals while insulin-dependent recruitment of the non-receptor tyrosine kinase Lyn to IRS-1 was enhanced under conditions of obesity. Thus, the focus of the proposed continuation of this project will be on the functional validation of reduced IRS-1/14-3-3 epsilon and enhanced IRS-1/Lyn interaction under obesity conditions as well as the elucidation of insulin-stimulated IRS protein complexes in other insulin target tissues with a specific emphasis on the CNS.
Running time: 07/2003 – 06/2015
Recent publications:
Wunderlich, F.T., Ströhle, P., Könner, A.C., Gruber, S., Tovar, S., Brönneke, H.S., Juntti-Berggren L., Li, L.S., van Rooijen, N., Libert, C., Berggren, P.O., Brüning, J.C. (2010). Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab. 12, 237-249.
Belgardt, B.F., Mauer, J., Wunderlich, F.T., Ernst, M., Pal, M., Spohn, G., Brönneke, H., Brodesser, S., Hampel, B., Schauss, A., and Brüning, J.C. (2010). Hypothalamic and pituitary JNK1 signaling coordinately regulates glucose metabolism. Proc. Natl. Acad. Sci. U.S.A. 107, 6028-33.
Kleinridders, A., Schenten, D., Könner, A.C., Belgardt, B.F., Mauer, J., Okamura, T., Wunderlich, F.T., Medzhitov, R., and Brüning, J.C. (2009). MyD88 signalling in the CNS is required for de-velopment of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab. 10, 249-59.
Kleinridders, A., Pogoda, H.M., Irlenbusch, S., Smyth, N., Koncz, C., Hammerschmidt, M., and Brüning, J.C. (2009). PLRG1 is an essential regulator of cell proliferation and apoptosis during vertebrate development and tissue homeostasis. Mol. Cell Biol. 29, 3173-85.
Wunderlich F.T., Luedde T., Singer S., Schmidt-Supprian M., Baumgartl J., Schirmacher P., Pasparakis M., and Brüning, J.C. (2008). Hepatic NF-kappaB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proc. Natl. Acad. Sci. U.S.A. 105, 1297-302.