Professor & Vice Chair of Biochemistry and Biophysics
Professor of Pharmacology (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.
- 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.
- Heenan, E. J., Vanhooke, J. L., Temple, B. R., Betts, L., Sondek, J. E., Dohlman, H. G., Structure and function of Vps15 in the endosomal G protein signaling pathway. Biochemistry 48:6390-401, 2009.
- Torres, M. P., Lee, M. J., Ding, F., Purbeck, C., Kuhlman, B., Dokholyan, N. V., Dohlman, H. G., G protein mono-ubiquitination by the Rsp5 ubiquitin ligase. J. Biol. Chem. 284:8940-50, 2009.
- Hao, N., Zeng, Y., Elston, T. C., and Dohlman, H. G., Accelerated Publication: Control of MAPK specificity by feedback phosphorylation of a shared adaptor protein Ste50. J. Biol. Chem. 283:33798-802, 2008.
- Hao, N., Nayak, S., Behar, M., Shanks, R. H., Nagiec, M. J., Errede, B., Hasty, J., Elston, T. C., and Dohlman, H. G., Regulation of cell signaling dynamics by the protein kinase-scaffold Ste5. Molecular Cell 30:649-56, 2008.
- Lee, M. J., and Dohlman, H. G., Co-activation of G protein signaling by cell-surface receptors and an intracellular exchange-factor. Current Biology 18:211-5, 2008.
- Behar, M., Hao, N., Dohlman, H. G., and Elston, T. C., Dose-to-duration encoding and signaling beyond saturation in intracellular signaling networks'. PLoS Compu. Biol. 4:e1000197, 2008.
120 Mason Farm Rd,
Campus Box # 7260
3046 Genetic Medicine
Chapel Hill, NC 27599
Lab Location: 3049 D-E Genetic Medicine