“The open-closed dynamics of Ga-subunits: implications to signaling and disease”
Dr. Roger Ken Sunahara | University of California, San Diego
Speaker bio:
Professor Sunahara received his graduate training with Dr. Philip Seeman in the Department of Pharmacology at the University of Toronto. He later joined the laboratory of eminent biochemical pharmacologist, Dr. Alfred G. Gilman, at the University of Texas Southwestern Medical School as a post-doctoral fellow. His training has provided a strong foundation and appreciation for the applications of pharmacology, biochemistry and structural biology to delineate mechanisms of action. Professor Sunahara started his independent research career in the Department of Pharmacology at the University of Michigan Medical School, where he climbed the academic ladder. In 2015 Professor Sunahara moved his laboratory to the Department of Pharmacology at the University of California in San Diego. His main area of research focuses on the structural and pharmacological bases for hormone-mediated activation of G proteins by G protein-coupled receptors (GPCRs).
Abstract:
G protein-coupled receptors (GPCRs), the largest family of signaling receptors and important drug targets, regulate complex signaling pathways through modulating effectors such as adenylyl cyclase, phospholipase C and ion channels. GPCRs also serve as major transcriptional regulators involving protein kinase A (PKA), extracellular- regulated kinase (ERK), the Hippo pathway and others. Recently, my laboratory has been focusing on the conformational changes in the stimulatory G protein G s , during receptor coupling focusing on ERK signaling. In particular, we are focusing on domain opening of Ga s , commonly observed in the nucleotide-free states of Ga subunits. I will discuss how point mutations in two splicing factors, the most common mutations found in myelodysplastic syndrome (MDS), specifically enhance the expression of the long splice form Ga s (long), but not Ga (short). MDS is a devastating disease resulting from a defect in hematopoietic cell differentiation. Enhanced expression of Ga s (long), but not Ga s (short), enhances basal ERK activation and is compounded by mutations in Ga s that are commonly found in cancer (R201C/H). Using an innovative Ga s fluorescent biosensor we also demonstrate that these cancer-related mutations stabilize the open conformation and that the effects of these mutations on domain opening appears to be greatest on Ga s (long) over Ga s (short). In a separate study we also recently reported that b 2 AR-stimulated ERK activation occurs on endosomes and not on the plasma membrane, as previously hypothesized. The ERK activation is dependent on arrestin for agonist-catalyzed endocytosis but requires Ga s on endosomes to activate cRAF, the upstream kinase of ERK. Moreover, Ga s -mediated activation of ERK occurs with Ga s (long), but not Ga s(short), consistent with the MDS study. Our data clearly indicate that the ERK activation originates on endosomes and progresses to the nucleus to regulate transcription of cMyc. Taken together these data shed light on the significance of the open conformation of Ga subunits to signaling and not just to nucleotide exchange. Moreover, it identifies endosomal Ga s as the primary modulator of the ERK pathway through Gs-coupled GPCRs.
