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Marino Zerial
Molecular mechanisms of intracellular transport
Previous and current research
Our group is interested in the molecular mechanisms of endocytosis, an essential function of all eukaryotic cells. We focus on 1) the mechanisms of endosome biogenesis, 2) how endocytic transport regulates and, in turn, is regulated by signalling molecules and 3) the regulation of endocytosis in polarised cells. Much of our progress originated from work on the small GTPase Rab5. By directing a network of over 30 effectors, Rab5 integrates various functions in vesicle formation, tethering and fusion, microtubule-dependent motility of early endosomes and signal transduction. Based on the analysis of Rab5, we have formulated a model whereby Rab-GTPases organize a mosaic of intercommunicating membrane domains, Rab-domains, providing functional identity to cellular organelles
Future prospects and goals
We aim at a comprehensive understanding of endosome function with respect to
organelle biogenesis, signal transduction and cell polarity, capitalizing on
our progress on the Rab machinery and further extending the molecular analysis
to novel regulatory components. Our aims are the following:
1. A major focus of our group is the study of endosome dynamics in living cells.
We rely on fast live cell imaging techniques with subsequent analysis and quantification
using a software package developed in our group. Such combination of high-end
imaging and advanced image analysis methodologies offers a unique entry point
into fundamental aspects of membrane trafficking. Current projects include the
study of cargo- and machinery dynamics during endosomal transport, endosome movement
along cytoskeletal tracks and continuous refinement of our image analysis algorithms.
2. A further challenge is the cognitive analysis of high-throughput genome-wide RNA interference screens to identify novel regulatory components of the endocytosis and signalling machinery. We have developed algorithms for quantifying compartment morphology, subcellular distribution and colocalization in the large image sets resulting from high-throughput screens. These tools will provide a basis for the development and implementation of new algorithms allowing supervised and non-supervised quantitative phenotype definition. Reconstructing regulatory networks and developing a systems biology approach to endocytosis (collaboration with Prof. A. Deutsch, TU-Dresden) provide another challenging task for scientists with a background in physics or computer sciences.
3. Cell polarity: we have been pursuing the identification and functional characterization of novel molecules regulating endocytic transport in C. elegans, D. melanogaster, zebrafish and mice).
4. We have discovered a novel specialized endosome devoted to signalling (see figure). We are currently investigating the role of this new compartment during development.
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Selected publications
Miaczynska, M., Christoforidis, S., Giner, A., Shevchenko, A.,
Uttenweiler-Joseph, S., Habermann, B., Wilm, M., Parton, R.G., and
Zerial, M. (2004): APPL Proteins Link Rab5 to Nuclear Signal Transduction via an Endosomal Compartment. Cell 116, 445-456.
Hoepfner, S., Severin, F., Cabezas, A., Habermann, B., Runge, A., Gillooly, D., Stenmark, H., and Zerial, M. (2005): Modulation of receptor recycling and degradation by the endosomal kinesin KIF16B. Cell 121, 437-50.
Pelkmans, L., Fava, E., Grabner, H., Hannus, M., Habermann, B., Krausz, E., and Zerial, M. (2005): Genome-wide analysis of human kinases in clathrin- and caveolae/raft-mediated endocytosis. Nature 436, 78-86.
Pelkmans, L., and Zerial, M. (2005): Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae. Nature 436, 128-33.
Rink, J., Ghigo, E., Kalaidzidis, Y., and Zerial, M. (2005): Rab conversion as a mechanism of progression from early to late endosomes. Cell 122, 735-49.