GPCRs are the largest family of membrane bound signaling molecules and, collectively, the target of many drugs currently used in the clinic. Classically, GPCRs were thought to be active at the cell surface and inactive while undergoing molecular sorting and trafficking events within the cell. Recent work has overturned this model. GPCRs are not quiescent inside of cells. Instead, it is now known that GPCRs can activate G protein signaling from many intracellular compartments including the endosome, and this intracellular signaling changes drug response. While efforts are already underway to harness endosomal GPCR signaling as a drug target, much is unknown about GPCR sorting at endosomes and how these trafficking processes control endosomal GPCR signaling. The goal of this proposal is to address the knowledge gap surrounding GPCR sorting at endosomes, and to determine how these pathways control endosomal signaling. In Project 1 we test the hypothesis that endosomal sorting functions as a kinetic timer to control GPCR signaling at endosomes. We examine a prototypical GPCR, the beta 2 adrenergic receptor, and the use a combination of genetic engineering and proteomics to determine how sorting controls endosomal signaling. In Project 2 we focus on two different GPCRs which signal at endosomes but lack any of the consensus endosomal sorting motifs. We use a combination of chemical biology, genomics, and proteomics to identify the proteins and pathways which mediate endosomal sorting of these receptors. Our studies seek to reveal fundamental lessons about conserved cell biological pathways while driving forward a new area for future GPCR drug development.
G protein-coupled receptors (GPCRs) are the target of more than a third of drugs current prescribed in the clinic, and new GPCR targeting therapeutics hold the potential to significantly improve human health. Recent breakthroughs have identified a population of GPCRs which signal from endosomes as a new therapeutic drug target. Toward this end, we seek to understand the fundamental mechanisms of GPCR sorting and signaling at endosomes. By understanding how these processes operate, our studies aim to guide future drug development targeting endosomal GPCR signaling.
