Eukaryotic cells respond to environmental cues by remodeling the cell surface, a process that relies on the targeted removal and degradation of plasma membrane (PM) proteins. This turnover process begins when a transmembrane PM protein (or "cargo") is ubiquitinated, a modification that is recognized by the endocytic machinery and sorted into vesicles. By targeting PM proteins for endocytosis, the cargo ubiquitination machinery directly regulates signaling processes, ion and nutrient homeostasis, stress responses, and protein quality control at the PM. Given that these processes are critical for cell growth and differentiation, it is not surprising that many human disease states, including various cancers, are associated with defects in PM protein turnover.
The main research objective of my lab is to understand the molecular mechanisms that regulate the composition of proteins at the plasma membrane and to engineer new technologies for artificial remodeling of the cell surface.
Cell Surface Remodeling in Yeast
In yeast, ubiquitin-mediated endocytosis is regulated almost exclusively by a ubiquitin ligase called Rsp5, a member of the Nedd4 family ubiquitin ligases. Rsp5 substrate selection is mediated by a modular adaptor network of proteins called ARTs which function to target Rsp5 ubiquitin ligase activity to specific substrates at the cell surface. My lab is focused on understanding (i) the molecular mechanisms that govern regulation of the ART-Rsp5 network and (ii) the biochemical and structural basis of ART-mediated cargo recognition. By dissecting the molecular mechanisms that drive cell surface remodeling in yeast, we hope to better understand cellular strategies for management of biological complexity.
Cell Surface Remodeling in Human Disease
The human genome encodes nine Nedd4 family ubiquitin ligases and many of these have been linked to various human diseases, including cancer. Despite their relevance to human disease, the biological function of many of these ubiquitin ligases is not well understood. Preliminary experiments indicate that networks of adaptor proteins, similar to the ART proteins in yeast, may function to target Nedd4 ubiquitin ligases to specific PM substrates. By characterizing the molecular mechanisms that govern the targeting of Nedd4 ubiquitin ligases in normal and disease states, we aim to develop new technologies that alter cell surface protein composition and explore these as potential tools for therapeutic intervention.