In my laboratory we study the molecular mechanisms of desensitization. Our primary focus is the regulation of
G proteins, which transmit signals from cell surface receptors to intracellular targets. G protein-coupled receptors
bind to neurotransmitters (e.g. adrenaline), peptide hormones (e.g. opiods), odors, taste and light. Genetic defects
in these pathways can cause a variety of developmental and metabolic disorders, including cancer, obesity, narcolepsy,
drug addiction, and resistance to HIV infection.
G proteins are highly conserved and are even found in the simplest eukaryotes, such as the yeast Saccharomyces
cerevisiae. We are currently using genetic screens to identify mutants with altered signaling and desensitization
properties in yeast. Such mutants are then characterized biochemically, both in yeast and in human cells (using h
omologous components). This approach has led to the discovery of a new family of desensitization factors, called RGS
proteins (Regulator of G protein signaling). RGS proteins promote G protein inactivation through their ability to
accelerate their GTPase activity. Presently we are using (i) genomics approaches to identify new desensitization
factors and their homologues in humans, (ii) proteomics approaches such as mass spectrometry to determine how
signaling proteins are regulated through post-translational modifications, (iii) as well as computational and
systems biology approaches to identify possible new feedback regulatory mechanisms.
Recent Publications:
Wang, Y., and Dohlman, H. G. (2006) Pheromone-regulated sumoylation underlies the invasive-to-mating transcription switch in yeast. J Bio. Chem 281(4): 1964-69. Abstract
Wang, X., Hao, N., Dohlman, H. G., and Elston, T. C. (2006) Bistability, stochasticity and oscillations in the mitogen activated protein kinase cascade. Biophys J 90: 1-19. Abstract
Parnell, S.C., Marotti, L.A. Jr., Kiang, L., Torres, M.P., Borchers, C.H., and Dohlman, H.G. (2005) Phosphorylation of the RGS protein Sst2 by the MAP kinase Fus3 and use of Ss2 as a model to analyze determinants of substrate sequence specificity. Biochemistry 44(22): 8159-66. Abstract
Wang, Y., Marotti, L.A. Jr., Lee, M.J., and Dohlman, H.G. (2005) Differential regulation of G protein alpha subunit trafficknig by mono- and polyubiquitination. J Biol Chem 280(1):284-91. Abstract
Wang, Y., and Dohlman, H. G. (2004) Pheromone signaling mechanisms in yeast: a prototypical sex machine. Science 306(5701): 1508-1509. Abstract
