| Description |
We have been using a multi-disciplinary approach to study the molecular principles underlying endosome biogenesis, transport and signaling. We have previously demonstrated that the small GTPase Rab5 is a master regulator of endosome function, orchestrating the membrane recruitment and activity of a multi-protein and lipid machinery responsible for membrane tethering, fusion and motility. A systems analysis of endocytosis revealed design principles of the endosomal network. This led us to formulate the “funnel model” that makes predictions on the progression of cargo through endosomes from the cell periphery to the cell centre over time. This work has further revealed that cells accurately regulate the number of EGF endosomes, their size, concentration of EGF and intracellular position. We have found that the packaging of phosphorylated EGFR in endosomes serves to regulate the extent, duration and robustness of the signaling response. We are now applying an imaging and quantitative image analysis approach to explore the mechanisms underlying cell and tissue organization at the multi-scale level using the liver as model system. We can apply molecular perturbations, e.g. gene silencing, on liver tissue organization and function. Using this approach, we have studied the effects of Rab5 depletion ranging from the molecular to the whole body physiology levels. This strategy can now be expanded to different genes, aiming at a multi-scale analysis of liver tissue organization and function.
|