This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Endocytic trafficking is key to multiple cellular functions. Upon ligand binding, the internalization and intracellular itineraries of cell surface receptors is critical to their ability to regulate a wide variety of critical processes, including nutrient uptake, cell adhesion, cell migration, and receptor signaling. Internalization occurs mostly in a manner dependent upon clathrin and the AP-2 adaptor complex. However, a growing list of receptors has been reported to internalize in a clathrin-independent manner. One subset of these receptors is known as Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs), a diverse family of proteins that undergoes a post-translational modification linking them covalently to the GPI. GPI-APs, which lack cytoplasmic tails, are organized within membranes that are enriched with cholesterol and sphingolipids, and these regions are known as """"""""rafts"""""""", due to their buoyancy in biochemical gradient fractionations. Here, we hypothesize that the newly identified C-terminal Eps15 homology domain (EHD) proteins play critical roles in GPI-AP trafficking. We provide compelling preliminary evidence for a novel function of EHD1 in the transport of GPI-APs from early endosomes to the endocytic recycling compartment, and address the mechanisms by which regulation of GPI-AP endocytosis occurs. Since GPI-APs are critical for multiple cellular processes like complement reactions, parasite entry and cell migration, an enhanced understanding of GPI-AP trafficking is of critical importance.
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