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The Ketteler lab is interested in the regulation of cancer signaling pathways. We employ high-throughput screening and novel biomolecular tools to investigate growth factor signaling cascades and to identify therapeutic targets for anti-cancer strategies. The two main research projects are:
1) Identification of novel Grb2 mediated signaling pathways
The small adaptor molecule Grb2 links growth receptor signaling to intracellular signal transduction cascades such as the MAP kinase pathway. In order to identify novel growth factor receptors and mediators, we use whole genome high-throughput screening approaches utilizing cDNA expression vectors and siRNA knockdown libraries. Grb2 tagged with the green fluorescent protein serves as a cellular marker for functional translocation upon activation of surface receptors or direct binding to Grb2. This approach enabled us to identify several novel binding partners for Grb2 that we currently characterize in further detail. For an overview of the methods used, please click here.
In order to better characterize image-based screening data, we are developing bioinformatic tools to identify and classify sub-cellular structures in high-throughput screening applications using 3D segmentation and visualization tools.
2) Identification of signaling cascades that regulate autophagy as therapeutic opportunity
Autophagy is an evolutionary conserved protein degradation pathway that is essential for cellular homeostasis and cell viability. Autophagy is enhanced under nutrient-limiting conditions such as amino acid starvation and can be induced by treatment with rapamycin, an inhibitor of the mammalian TOR complex. Autophagy has been implicated in tumour suppressive, as well as tumour promoting mechanisms. The molecular regulation of autophagy is not very well understood.
We have recently developed a cell-based assay for autophagy that is amenable to high-throughput screening. The method measures proteolytic cleavage of a tripartite sensor protein by the autophagy protease ATG4B. Activation of ATG4B results in release of Gaussia luciferase from cells that can be non-invasively harvested from cellular supernatants. In order to better understand the signaling cascades involved in the activation of autophagy, we are screening whole genome siRNA libraries for factors that enhance or reduce the activity of ATG4B. In addition, we are performing small molecule library screening to identify potential therapeutic lead compounds.
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