My 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. In order to better characterize image-based
screening data, we are designing bioinformatic tools to classify molecular
translocations with respect to the cellular localization.

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 by overexpression or treatment
with rapamycin 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.