Welcome to the Ketteler lab website! If you are interested in our research, please stay on this site. If you are interested in the high-throughput screening services that we offer, please click here.
The Ketteler lab is interested in signal transduction pathways
and the regulation of autophagy. We employ high-throughput screening platforms
using cDNA, siRNA and CRISPR libraries to investigate growth factor signaling
cascades and identify therapeutic targets for cancer and neuro-degeneration.
Classical EGFR signaling involves the binding
of adaptor molecules such as Grb2 to the receptor and converts an extracellular
signal into an intracellular response. This signal conversion involves
protein-protein interactions and activation of intracellular signaling complexes
through post-translational modifications. We and others have recently developed
novel assays that enable the characterization of these signaling cascades in a
systematic manner. We utilize a mammalian two-hybrid system, originally
developed by Julia Petschnigg and Igor Stagljar, in order to identify novel
EGFR interaction partners (Petschnigg et al. 2014). Julia recently joined my
lab to introduce this technique at the LMCB. In combination with a previously
developed assay from our lab to identify localized signaling via the adaptor
Grb2 (Freeman et al. 2012), we were able to identify novel genes involved in
trafficking and signaling of the EGFR.
The main findings so far are:
1. A large
number of genes was identified that bind to Grb2 or to the EGFR that were
previously not implicated in signalling via this pathway.
2. Some genes
were shown to preferentially interact with oncogenic versions of the EGFR when
compared to wild-type EGFR.
complexes were identified in unexpected subcellular locations such as the
nucleus, the centrosome, autophagosomes and sites of protein aggregation.
These studies indicate that very little is
known about the spatial and temporal regulation of classical signalling
pathways that we plan to address in the future.
Autophagy is a cellular stress response to
diverse stimuli such as starvation, infection and DNA damage. Despite recent
advances in our understanding of the autophagy machinery, the molecular
regulation of autophagy is not very well understood. We are interested in
understanding how autophagy core proteins are controlled by post-translational
modifications. In particular, we are interested in the regulation of autophagy
by kinase signaling. Using a luciferase-based assay and siRNA screening
(Ketteler et al. 2008; Ketteler and Seed, 2008), we have identified genes that
regulate the cellular activity of ATG4B. We have identified multiple kinases
and phosphatases that regulate ATG4B activity and autophagosome formation. The
main findings so far are:
kinases and phosphatases were identified that control the proteolytic activity
of ATG4B and the formation of autophagosomes.
activity is controlled locally by phosphorylation/de-phosphorylation events
with an inhibitory phosphorylation at the autophagosome initiation site and an
activating de-phosphorylation at the autophagosome-lysosome fusion site.
The local control of autophagy signalling is
very intriguing and forms the basis for future studies where we aim to
understand this in more mechanistic detail.
Autophagy plays important roles in the
progression of various diseases including cancer and Parkinson’s disease. In
particular, it has been proposed that the up-regulation of autophagy in
neuro-degenerative diseases can be benefitial for neuron survival. We have
completed a small molecule screen of ~50,000 compounds in order to identify
chemical compounds that target either ATG4B directly or autophagosome formation
in general. Through various collaborations with chemists and bioinformaticians,
we have identified four main classes of compounds:
These compounds can find applications in
various disease models such as cancer and neuro-degeneration.
Our work has been supported by the Medical
Research Council, BBSRC, Wellcome Trust, Michael J Fox Foundation and
University College London CiC/TIF funding.
Back to Molecular Cell Biology.
Number of publications: 49.