Dynamics and functional roles of post-translational modifications of seven-transmembrane G protein-coupled receptors and β-arrestins.
Our lab is interested in understanding the roles of ubiquitination in G protein-coupled receptor trafficking and signal transduction. Both the receptor and the associated adaptor called β-arrestin become ubiquitinated in an agonist-dependent manner and in each case the modification directs a specific functional consequence: receptor ubiquitination allows the internalized receptor to be sorted into lysosomes for degradation, and β-arrestin ubiquitination allows efficient protein-protein interaction facilitating its multifaceted role in endocytosis and signaling. We have identified the cognate E3 ubiquitin ligases that ubiquitinate the β2 adrenergic receptor and β-arrestin2, and we have also identified the deubiquitinases (DUBs) that reverse these modifications. Current projects in the lab are aimed toward answering the following questions: (1) Is β-arrestin ubiquitination important for βAR signaling in the heart? (2) Does β-arrestin2 serve as a DUB adaptor in signaling? (3) Is DUB activity modulated upon GPCR activation, if so how? In addition to in vitro experimental systems, we are also working on transgenic and knockout mice to determine the physiological relevance of ubiquitination/deubiquitination dynamics in GPCR signaling.