The Rab GTPases are a large family of proteins with a variety of regulatory functions in membrane traffic. The central role of these proteins has become clear during the past decade, as part of the progress in understanding in detail the mechanistic principles of transport vesicle formation, movement, and fusion. Sequencing of the human genome has allowed us to realize the diversity of the Rab gene family, though the functions of a majority of the gene products are unknown. The availability of complete genomic sequences, as well as important advances in molecular and cell biological methods, promise to bring a significant progress in our understanding of Rab function in the near future.
At the molecular level, the identification of novel GAPs, GEFs and effectors will yield information about the regulation of Rab GTPases and the molecular complexes they control. Crosstalk with regulatory mechanisms involving other members of the Ras GTPase superfamily is already becoming apparent. A key question concerns the targeting of the Rab GTPases. Which 'receptor' molecules determine their specific intracellular distributions? A combination of biochemical and genetic approaches will hopefully illuminate this issue.
At the level of the membrane, several aspects of Rab GTPase function remain to be clarified. Are Rab GTPases confined to restricted membrane domains [3
] and, if so, how is this determined? Furthermore, how do Rab GTPases and their effectors regulate membrane budding, motility and fusion? With respect to membrane fusion, the role of Rab effectors as membrane tethers is already being revealed, and it seems realistic to expect that Rab-dependent membrane fusion may be reconstituted in vitro
from purified components in the near future.
Finally, comprehending the ways in which the regulatory actions of Rabs intertwine with cell-signaling cascades and developmental processes is an enormous task for cell biologists. Here, the natural mutant models provided by human genetic diseases that have defects in Rabs or their auxiliary proteins, as well as the novel genome-wide approaches for gene expression analysis, will be instrumental.