RabGTPasesMarkTargetsInTheEndocytoticMachinery

The eukaryotic cell contains compartments with distinct functions bounded by lipid bilayer membranes. The movement of membrane vesicles between these compartments allows proteins in the secretory pathway to move outward from the endoplasmic reticulum (ER) to the Golgi, trans Golgi network (TGN), secretory vesicles, and the plasma membrane and to be secreted into the extracellular environment. The trafficking of membrane vesicles is also essential for endocytosis and the movement of material from the extracellular environment into the early endosome (EE), late endosome (LE) and lysosome. The movement of vesicles and their contents between these compartments and their secretion are essential for a host of cellular functions, including the release of neurotransmitters and hormones. The movement of membrane vesicles between all of these compartments is regulated by members of the Rab family of GTPases, part of the ras superfamily of genes, regulated through binding of GTP and hydrolysis of bound GTP to GDP. At least eleven yeast genes in this family have been identified as Ypts, yeast transport proteins, and over sixty mammalian Rab genes have been identified in this highly conserved gene family. The products of the Rab genes regulate specific steps in vesicle transport. Rab1 is involved in the movement of membranes from the ER through the Golgi. Rab3 regulates secretory vesicle release and Rab27 is also involved in regulated release of secreted proteins. Rab5, 7 and 9 contribute to endocytosis while Rab4 and Rab11 mediate recycling from the endosome back to the plasma membrane. Rab11 is involved in both endocytosis and exocytosis. As with other Ras family GTPases, the activity of Rabs is regulated by guanine-nucleotide exchange factors (GEFs) and GAPs (GTPase activating proteins). Downstream effectors must also interact with Rabs to transmit their signals regulating each step of the membrane trafficking pathways including vesicle formation, movement of vesicles between compartments, vesicle docking, fusion and membrane remodeling. Downstream effectors of the Rabs include Rabphilin-3 (vesicle movement effector for Rab3), Rabphilin-11 (vesicle formation effector for Rab11), and EEA1 (vesicle fusion and membrane remodeling). If Rabs are involved in more than one role and other components of Rab signaling also interact with more than one Rab this will further increase the complexity of the system. Elucidating the interaction of Rabs and regulation of vesicle trafficking by other signaling pathways will be a key area of research in the future.

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