Sanford Steelman Distinguished Professor and Chair, Department of Pharmacology
Biochemistry & Biophysics – joint appointment
(PhD – Duke University)
HONORS AND AWARDS
- Associate Editor, Journal of Biological Chemistry, 2013
- Fellow, American Association for the Advancement of Science, 2011
- Established Investigator, American Heart Association, 1998
- Jane Coffin Childs Memorial Fund Fellowship, 1989
Mechanisms of Cell Desensitization: Regulators of G protein Signaling.
Our research is centered on G proteins and G protein-coupled receptors (GPCRs). GPCRs are the target of nearly half of all pharmaceuticals, as well as light, taste, odors, hormones and neurotransmitters. Generally speaking, persistent stimulation of G proteins leads to desensitization. Familiar examples include desensitization to light, odors and chemical stimulants such as caffeine.
Receptors, G proteins, and effector MAP kinases are conserved in evolution and are even found in the simplest eukaryotes such as the yeast Saccharomyces cerevisiae. We have been conducting large-scale genomic and proteomic analysis in yeast to identify mutants with altered signaling and desensitization properties. Such mutants are then characterized biochemically in yeast as well as in animal cells using homologous components. This approach led to the identification in yeast of a family of desensitization factors called RGS proteins (Regulator of G protein signaling). RGS proteins inactivate G proteins by accelerating their intrinsic GTPase activity
Thus, RGS proteins serve as the molecular ‘brakes’ in cell signaling: they diminish our sensitivity to environmental signals, neurotransmitters and pharmaceuticals over time.
Building on the RGS work, we are currently investigating how other regulatory processes (e.g. feedback phosphorylation, protein ubiquitination, and intracellular pH changes) can limit activation of competing parallel signaling pathways. Efforts in collaboration with Tim Elston’s group seek to construct computational models of constituent signaling networks and pathways. The long-term objective is to devise predictive models of signal transduction in more complex systems, and ultimately determine how specific stimuli or drugs will influence the signaling network, in addition to specific target enzymes or receptors.
- Isom DG, Dohlman HG. Buried ionizable networks are an ancient hallmark of G protein-coupled receptor activation. Proc Natl Acad Sci U S A. 2015 May 5;112(18):5702-7. doi: 10.1073/pnas.1417888112. Epub 2015 Apr 20. PubMed PMID: 25902551; PubMed Central PMCID: PMC4426463.
- Kelley JB, Dixit G, Sheetz JB, Venkatapurapu SP, Elston TC, Dohlman HG. RGS proteins and septins cooperate to promote chemotropism by regulating polar cap mobility. Curr Biol. 2015 Feb 2;25(3):275-85. doi: 10.1016/j.cub.2014.11.047. Epub 2015 Jan 15. PubMed PMID: 25601550; PubMed Central PMCID: PMC4318785.
English JG, Shellhammer JP, Malahe M, McCarter PC, Elston TC, Dohlman HG. MAPK feedback encodes a switch and timer for tunable stress adaptation in yeast. Sci Signal. 2015 Jan 13;8(359):ra5. doi: 10.1126/scisignal.2005774. PubMed PMID: 25587192.
- Dixit G, Kelley JB, Houser JR, Elston TC, Dohlman HG. Cellular noise suppression by the regulator of G protein signaling Sst2. Mol Cell. 2014 Jul 3;55(1):85-96. doi: 10.1016/j.molcel.2014.05.019. Epub 2014 Jun 19. PubMed PMID: 24954905; PubMed Central PMCID: PMC4142594.
- Dixit G, Baker R, Sacks CM, Torres MP, Dohlman HG. Guanine nucleotide-binding protein (Gα) endocytosis by a cascade of ubiquitin binding domain proteins is required for sustained morphogenesis and proper mating in yeast. J Biol Chem. 2014 May 23;289(21):15052-63. doi: 10.1074/jbc.M114.566117. Epub 2014 Apr 10. PubMed PMID: 24722989; PubMed Central PMCID: PMC4031556.
- Baker R, Wilkerson EM, Sumita K, Isom DG, Sasaki AT, Dohlman HG, Campbell SL. Differences in the regulation of K-Ras and H-Ras isoforms by monoubiquitination. J Biol Chem. 2013 Dec 27;288(52):36856-62. doi: 10.1074/jbc.C113.525691. Epub 2013 Nov 18. PubMed PMID: 24247240; PubMed Central PMCID: PMC3873545.
- Clement, S. T., Dixit, G., and Dohlman, H. G., Regulation of yeast G protein signaling by the kinases that activate the AMPK homolog Snf1. Science Signaling 6:ra78, 2013.
- Isom, D. G., Sridharan, V., Baker, R., Clement, S. T., Smalley, D. M., and Dohlman, H. G., Protons as second messenger regulators of G protein signaling. Molecular Cell 51:531-538, 2013.
- Hurst, J.H., and Dohlman, H. G., Dynamic ubiquitination of the mitogen-activated protein kinase kinase (MAPKK) Ste7 determines mitogen-activated protein kinase (MAPK) specificity. Journal of Biological Chemistry 288:18660-18671, 2013.
- Baker, R., Lewis, S. M., Wilkerson, E. M., Sasaki, A. T., Cantley, L. C., Kuhlman, B., Dohlman, H. G., and Campbell, S. L., Site-Specific Monoubiquitination Activates Ras by Impeding GTPase Activating Protein Function. Nature Structural & Molecular Biology 20:46-52, 2013.
- Lien, E., Nagiec, M. J., and Dohlman, H. G., Proper protein glycosylation promotes mitogen-activated protein kinase signal fidelity. Biochemistry 52:115-24, 2013.
- Fernandez-Piñar, P., Alemán, A., Sondek, J., Dohlman, H. G., Molina, M., and Martín, H., The Salmonella Typhimurium effector SteC inhibits Cdc42-mediated signaling through binding to the exchange factor Cdc24 in Saccharomyces cerevisiae. Molecular Biology of the Cell 23:4430-43, 2012.
- Hao, N., Yildirim, N., Nagiec, M. J., Parnell, S. C., Errede, B., Dohlman, H. G., and Elston, T. C., Combined computational and experimental analysis reveals MAP kinase mediated feedback phosphorylation as a mechanism for signaling specificity. Molecular Biology of the Cell 23:3899-910, 2012.
- Dohlman, H. G., and Jones, J. C., Signal activation and inactivation by the Gα helical domain: a long neglected partner in G protein signaling. Science Signaling 5(226):re2, 2012.
- Jones, J. C., Jones, A. M., Temple, B. R. S., and Dohlman, H. G., Differences in intradomain and interdomain motion confer distinct activation properties to structurally similar Gα proteins. Proceedings of the National Academies of Sciences USA 109:7275-9, 2012.
- Cronan, M. R., Johnson, N. L., Granger, D. A., Cuevas, B. D., Nakamura, K., Dohlman, H. G., and Johnson, G. L., Defining MAP3Kinases required for MDA-MB-231 cell tumor growth and metastasis. Oncogene 31:3889-900, 2012.
- Nagiec, M. J., and Dohlman, H. G., Checkpoints in a yeast differentiation pathway coordinate signaling during hyperosmotic stress. PLoS Genetics, 8(1): e1002437 doi:10.1371/journal.pgen.1002437) 2012.
- Jin, M., Errede, B., Behar, M., Mather, W., Nayak, S., Hasty, J., Dohlman H. G., and Elston, T. C., Yeast dynamically modify their environment to achieve better mating efficiency. Science Signaling, 4:ra54, 2011.
- Zhu, M., Torres, M. P., Kelley, J., Dohlman, H. G., and Wang, Y., Pheromone- and Rsp5-dependent ubiquitination of the G protein beta subunit Ste4 in yeast. J. Biol. Chem., 286:27147-55, 2011.
- Torres, M. P., Clement, S. T., Cappell, S. D., and Dohlman, H. G., Cell cycle-dependent phosphorylation and ubiquitination of a G protein alpha subunit. J. Biol. Chem. 286:20208-16, 2011.
- Cappell, S. D., Dohlman, H. G., Selective regulation of MAP kinase signaling by an endomembrane phosphatidylinositol 4-kinase. J. Biol. Chem. 286:14852-60, 2011.
- Jones, J. C., Temple, B. R. S., Jones, A. M., Dohlman, H. G., Functional reconstitution of an atypical protein heterotrimer and regulator of G protein signaling (RGS) protein from Arabidopsis thaliana. J. Biol. Chem. 286:13143-50, 2011.
- Jones, J. C., Duffy, J. W., Machius, M., Temple, B. R. S., Dohlman, H. G., Jones, A. M., The crystal structure of a self-activating G protein alpha-subunit reveals its distinct mechanism of signal initiation. Science Signaling 4:ra8, 2011.
- Cappell, S. D., Baker, R., Skowyra, D., Dohlman, H. G., Systematic analysis of essential genes reveals important regulators of G protein signaling. Molecular Cell 38:746-57, 2010.