Our group is interested in the molecular mechanisms of endocytosis, an essential function of all eukaryotic cells. In particular, we have been focusing on three aspects: 1) the mechanisms underlying endosome biogenesis, 2) how endocytic transport regulates and is modulated by intracellular signalling and 3) the regulation of endocytosis in polarised cells, such as epithelial cells and neurons. Much of our progress originated from work on Rab GTPases, in particular Rab5. Rab5 is a rate-limiting regulator of endocytic membrane dynamics that function both in transport from the plasma membrane to the early endosomes as well as in homotypic endosome fusion. A breakthrough in elucidating the function of Rab5, and Rab GTPases in general, has come from the biochemical purification and functional characterization of a large molecular network of effector proteins, each contributing a specific function in vesicle formation, tethering and fusion, as well as in the microtubule-dependent motility of early endosomes. Some examples of these studies are provided below. To date, the Rab5 machinery comprehends the largest number of effector molecules associated with a single small GTPase.

Based on the analysis of Rab5 effectors, we have formulated a new model to explain the organization and biogenesis of early endosomes. The model proposes that endosomes are organized as a mosaic of distinct membrane compartments termed Rab-domains. Each Rab-domain is created through the recruitment of effector proteins, which generate a spatially restricted and functionally specialized environment on the membrane. Divalent Rab effectors are responsible for the sequential communication between adjacent Rab-domains (e.g. from Rab5 to Rab4, from Rab4 to Rab11). Thus, a kind of “binary switch” system allows cargo to be sequentially transported along the endocytic/recycling pathway. We propose that the Rab-domain organization of early endosomes is a general principle underlying intracellular transport and organelle biogenesis in eukaryotic cells.

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The additional material accompanying the article

"Genome-wide analysis of human kinases in clathrin- and caveolae/raft-mediated endocytosis" by Lucas Pelkmans, Eugenio Fava, Hannes Grabner, Michael Hannus, Bianca Habermann, Eberhard Krausz & Marino Zerial.
Nature (May 11, 2005)

can be downloaded here [xls, 240 KB].