Appears in collection : From Molecules and Cells to Human Health : Ideas and concepts

The members of the RAB GTPase family (less than 60 proteins in man) are master regulators of intracellular transport and membrane trafficking in eukaryotic cells. RAB6 is one of the five ancestral RAB genes conserved from yeast to human. The RAB6 family comprises four proteins, named RAB6A, RAB6A’, RAB6B and RAB6C. The two ubiquitously expressed isoforms, RAB6A and A, are generated by alternative splicing of the same gene and localize to the Golgi complex. We and others have established that RAB6 regulates several transport pathways at the level of this organelle. Our recent work has focused on several aspects of RAB6 function: -The mechanisms involved in the fission of RAB6-positive transport carriers from Golgi/TGN (Trans-Golgi Network) membranes. We have previously shown that RAB6-Myosin IIA interaction is critical for this process [1]. Recently, we showed that the kinesin protein KIF20A is also involved in the fission process and serves to anchor RAB6 on Golgi/TGN membranes near microtubule (MT) nucleating sites. Our results suggest that the coupling between actin and MT cytoskeletons driven by Myosin II and KIF20A ensures the spatial coordination between the fission of RAB6-positive vesicles from Golgi/TGN membranes and their exit along microtubules [2]. - The role of RAB6 in post-Golgi transport. Using the RUSH system [3] and a variety of secretory cargos, including GPI-anchored proteins, TNF-alpha and Collagen-X, we found that RAB6 associates with post-Golgi vesicles containing all of these cargos. Depletion of RAB6 inhibits their arrival at the plasma membrane. These results suggest that RAB6 could be a general regulator of post-Golgi vesicles, possibly targeting secretory vesicles to defined exocytic sites on the cell surface [4]. -The role of RAB6 in cell lineages and tissues. We have generated mice with a conditional null allele of RAB6A [5]. The mice, which do not express RAB6A and RAB6A’, die at an early stage of embryonic development (day 5.5), indicating that RAB6A is an essential gene. The phenotype of RAB6A-/- embryos is very similar tothat of beta-1 integrin null embryos. This result is consistent with the finding that a pool of inactive integrins follows the retrograde pathway regulated by RAB6 and that this pathway is critical for adhesion and persistent cell migration [6]. The RAB6 k/o mice were crossed with several mouse lines to deplete RAB6 in various tissues or cell lineages. We will present data illustrating that RAB6 fulfills different functions depending on the cell or tissue context.