University of Nebraska Medical Center

Research Interests

Control of receptor localization to the plasma membrane is central to normal cell function, and dysregulation is the underlying cause for diseases as diverse as atherosclerosis, diabetes and cancer. For example, enhanced recycling of growth factor receptors has been implicated in pancreatic carcinoma, breast cancer and other epithelial tumors. Receptor levels on the plasma membrane depend on the rates of internalization and recycling back to the cell surface. Most recycled receptors are transported from early endosomes to the plasma membrane via a transitory recycling compartment, but the regulation of these steps remains poorly understood. 

The recently identified Eps 15 homology (EH)-domain containing proteins: EHD1, EHD2, EHD3, and EHD4, are critical components of the endocytic pathway. We and others have demonstrated distinct but partially overlapping functions for the four EHD proteins, in the endocytic trafficking of receptors internalized both through clathrin-dependent and independent mechanisms. However, the influence of EHD proteins on the regulation of a distinct family of receptors, those coupled to the plasma membrane by a glycosylphosphatidylinositol-(GPI) anchor and residing in cholesterol and glycosphingolipid-enriched rafts™, has yet to be addressed. GPI-anchored proteins (GPI-APs) contain a specific C-terminal signal sequence that allows the covalent coupling of a synthesized GPI moiety to the protein at the cytoplasmic face of the endoplasmic reticulum. The proteins themselves are highly diverse, and include growth factor receptors, adhesion molecules as well as hydrolytic enzymes, complement inhibitors and other key signaling proteins. In addition to signaling, certain GPI-anchored proteins such as the Carcinoembryonic antigen (CEA) family cell adhesion molecule member, CEACAM5, are human tumor markers that function in intercellular adhesion and are highly expressed in tumor cells. 

Given the overall significance of GPI-APs in cell signaling, and especially the role of GPI-APs such as CEA-family members in tumorigenesis, the regulation of intracellular trafficking of these proteins warrants a high level of attention. Most surprisingly, little is known about the molecular mechanisms by which CEACAM5 is internalized and recycled. The long-term goals of this project are to understand the fundamental mechanisms controlling intracellular trafficking and transport of GPI-APs through the endocytic pathways, with emphasis on understanding the mode by which EHD proteins regulate these events. Ultimately, these studies will lead to development of new strategies to treat diseases involving traffic and recycling events.