B4_Insulin Signalling

Department for Gastroenterology and Hepatology (University Hospital of Freiburg)
Dr. María Matilde Bartolomé Rodríguez (PL), Markus Nenniger (PhD student), Zuheir Mohamad Halima (MD student), Maximilian Seidl (MD student), Konrad Stürmer (MD student), Astrid Wäldin (TA)

Center for Data Analysis and Modelling (University of Freiburg)
Prof. Dr. Jens Timmer (PL), Dipl. Phys. Clemens Kreutz (PhD student)

Institute for System Dynamics (University of Stuttgart)
Markus Koschorreck (PhD student)

Project summary:

The enormous regeneration capacity of the liver is unique among mammals. Strikingly, during this intensive phase of proliferation, hepatocytes continue to ensure their essential metabolic functions such as glucose regulation, degradation of toxic compounds or synthesis of proteins. The hormone insulin is an essential factor in these processes inducing both proliferative and anti-apoptotic responses. In the presence of insulin, activation of their receptor tyrosine kinase creates binding sites for intracellular substrates such as IRS family of proteins and induces their phosphorylation. Phosphorylated IRS proteins are linked to the activation of two main signaling pathways: the PI3'AKT/protein kinase B (PKB) pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-mitogen-activated protein kinase (MAPK) pathway, which regulates the expression of several genes and cooperates with the PI3'kinase pathway to control cell growth and differentiation.

We focused our efforts on detailed recovery of dynamic, spatially resolved high quality data on insulin-induced signal transduction in primary murine hepatocytes with emphasis on phosphorylation of IR, IRS-1, PI3'kinase recruitment by IRS-1 and ERK1/2 activation as a basis for a first data-based model of insulin-induced signal transduction in primary hepatocytes. Hereby, both the data-quality as well as the reproducibility of quantitative measurements are the main bottleneck for their use in systems biology approaches like parameter estimation, simulation studies and model selection. For this reason, we developed strategies for the quantitative data generation though accurate analysis and quantification of errors leading to the introduction of a model for the elimination of systematic measurement errors in protein quantification. Further, a minimalistic, data-based model is being developed to explain the observed biphasic activation behavior on IR and IRS phosphorylation kinetics in collaboration with Prof. Gilles-Group (Project C1). Finally, the a nalysis of Insulin-EGF crosstalk-links as well as the influence of insulin on pro- and anti-apoptotic pathways will be studied in detail to better understand the tightly mechanisms involved in the hepatocyte regeneration.