Ypt/Rab GTPases: Regulators of Protein Trafficking

Ypt/Rab guanosine triphosphatases (GTPases) have emerged in the last decade as key regulators of protein transport in all eukaryotic cells. They seem to be involved in all aspects of vesicle trafficking: vesicle formation, motility, and docking, and membrane remodeling and fusion. The functions of Ypt/Rabs are themselves controlled by upstream regulators that stimulate both their nucleotide cycling and their cycling between membranes. Ypt/Rabs transmit signals to downstream effectors in a guanosine triphosphate (GTP)-dependent manner. The identity of upstream regulators and downstream effectors is known for a number of Ypt/Rabs, and models for their mechanisms of action are emerging. In at least two cases, Ypt/Rab upstream regulators and downstream effectors are found together in a single complex. In agreement with the idea that Ypt/Rabs function in all aspects of vesicular transport, their diverse effectors have recently been shown to function in all identified aspects of vesicle transport. Activators and effectors for individual Ypt/Rabs share no similarity, but are conserved between yeast and mammalian cells. Finally, cross talk demonstrated among the various Ypt/Rabs, and between Ypt/Rabs and other signaling factors, suggests possible coordination among secretory steps, as well as between protein transport and other cellular processes. In eukaryotic cells, an evolutionarily conserved transport system routes proteins through a number of highly regulated pathways. In these pathways, intercellular signaling proteins are released, receptors and transporters are presented on the outer cell membrane, and ligand-bound receptors are internalized. Therefore, the protein transport system is central to the interaction of cells with their environments. The passage of proteins through this transport system involves an orderly progression through a series of membrane-bound compartments. To be transported from one compartment to the next, proteins are packaged into small vesicles that bud from one compartment and fuse with the next. Like traffic lights at critical intersections, a family of proteins known as Ypt/Rab guanosine triphosphatases (GTPases) regulates vesicle formation, movement, attachment, and fusion at each transport step. These individual transport steps might be further coordinated by Ypt/Rabs through their communication with each other. GTPases in general serve as molecular switches that can be turned "on" or "off" by upstream regulators. Ypt/Rabs transmit their "on" signals through the recruitment and activation of multiple downstream effector proteins, which carry out the various functions necessary for vesicle transport. Numerous regulators and effectors of Ypt/Rab GTPases have been identified, leading to models that predict how they carry out their functions. This review summarizes the current knowledge about molecular mechanisms by which the Ypt/Rab switches perform their highly complex task.