Rab GTPases and Neuroendocytosis

University Of Texas Medical Branch At Galveston, Galveston TX

Investigators

Abstract

Internalization and recycling of cell surface receptors by endocytosis regulates the intensity and duration of a cell's response to environmental signals. Perhaps nowhere is endocytosis more important than in the nervous system. Here the balance between regulating receptor internalization with recycling back to the cell surface is crucial for modulating neuronal communication and cell function in general. Early, and Pericentriolar Recycling Endosomes are critical sorting compartments that receive endocytosed receptors from the cell surface. However, little is known about the molecular mechanisms regulating the transit of endocytosed receptors through these distinct compartments. Endosomal rab GTPases have emerged as critical regulators of endocytic trafficking. They function by recruiting unique combinations of membrane specific effectors that underlie the distinct functional properties of each endosomal compartment. The novel GTPase Rab15, has formed the focal point for ongoing studies in this laboratory because of its unique localization to Early Endosomes and Pericentriolar Recycling Endosomes, and its demonstrated importance in regulating receptor transport through these compartments. When over expressed in cells, Rab15 inhibits receptor transport through both types of endosomes, suggesting that Rab15 function at these distinct compartments requires specific effector interactions. Consistent with this hypothesis, two novel endosomal proteins, RBP15 and REP15, have been identified, which specifically interact with Rab15 in Early Endosomes and Pericentriolar Recycling Endosomes respectively. The proposed experiments will define the individual roles of these novel endocytic proteins in receptor trafficking, and delineate the molecular steps in which they participate. These aims will be achieved using a combination of complementary molecular, cellular and optical approaches. The proposed studies will increase our fundamental understanding of how Rab GTPaes and their effectors regulate receptor transport through Early Endosomes and Pericentriolar Recycling Endosomes, a process pivotal for synaptic function and cell function in general.