B5_HGF Signalling

IfADo (University of Dortmund)
Prof. Dr. Jan G. Hengstler (PL), Dr. Patricio Godoy (PhD)

DKFZ (Heidelberg)
PD Dr. Ursula Klingmüller (PL), Dr. Lorenza D'Alessandro (PhD), Bin She (PhD student)

Center for Data Analysis and Modelling (University of Freiburg)
Prof. Dr. Jens Timmer (PL)

Bioquant (University of Heidelberg)
Prof. Dr. Thomas Höfer (PL), Dr. Carlos Salazar (PhD)

Project summary:

Hepatocyte growth factor (HGF)/c-Met signaling promotes both proliferation and scattering (migration) of hepatocytes. Major signaling cascades activated upon ligand binding to the receptor tyrosine kinase c-Met are the MAP kinase and the phosphoinositide (PI)3 signaling cascades. Additionally, the STAT and the phospholipase C pathways are activated. Although the individual components of the involved signaling cascades have been studied intensively, their specific contribution to proliferation and migration of hepatocytes is poorly understood. Detailed time-resolved data for the activation of the MAP kinase signaling cascade will be generated by the group of J. Hengstler and used for mathematical modeling by the groups of R. Heinrich and J. Timmer refining existing kinetic descriptions of the core components. Control analysis will be used to identify key components controlling signal amplification and signal duration (Heinrich et al., 2002, Hornberg et al., 2005). The PI3 kinase signaling pathway will be examined by the group of U. Klingmüller by biochemical means and by live cell imaging. The time-resolved data will be used to extend the mathematical model established in collaboration with J. Timmer and finally used in combination with spatially resolved data to establish a spatio-temporal model. Model predictions will be experimentally verified by applying an RNAi strategy and by developing a tetracyclin inducible system that facilitates dose-dependent over-expression of signaling components and the expression of fluorescently labeled signaling molecules. A key signaling cascade activated during the proliferative phase of hepatocyte regeneration is the PI3 kinase cascade that is primarily triggered by the c-Met receptor in response to binding of HGF. The TGF-beta mediated activation of the SMAD signaling pathway is important during the termination phase of hepatocyte regeneration. Both signaling cascades cross-modulate their respective activity e. g. HGF stimulation of the c-Met receptor induces the production of TGF-beta, whereas TGF-beta stimulates the induction of a negative regulator of PI3 kinase signaling, the phosphoinositide-5-phosphatase SHIP-1, SMAD2/3 target gene. Elucidating systems properties governing the cross-talk of the signaling pathways will provide insight into mechanisms supporting the switch from the proliferation phase towards differentiation.