Robert J. Deschenes, Ph.D.
Joseph F. Heil, Jr. Professor and Chairman
Dr. Deschenes obtained his Bachelor of Science degree from St. Michaels College, a Masters of Science in Biochemistry from Tufts University, and his doctorate degree in Biochemistry from Purdue University. He then did postdoctoral training in the Molecular Biology department at Princeton University where he initiated studies on the posttranslational regulation of Ras oncogene proteins in the model organism yeast, Saccharomyces cerevisiae. Prior to joining the Medical College of Wisconsin, Dr. Deschenes was the Vice Chair of the Department of Biochemistry at the University of Iowa and director of the Genetics Ph.D. program. Dr. Deschenes joined the Department of Biochemistry at the Medical College in 2004. His research group studies eucaroytic signal transduction pathways involved in cancer and cell stress.
Contact Information
rdeschen@mcw.edu
Phone: (414) 456-8768
Fax: (414) 456-6510
Research Interests
The group's efforts are currently focused in two general areas. The first deals with the posttranslational modification and the subcellular localization of signal transduction proteins. The second deals with stress signaling and the characterization of histidine kinases.
Posttranslational modification and subcellular localization of Ras proteins. It has been known for some time that Ras undergoes posttranslational addition of lipids and this is required for subcellular localization and the signaling functions of Ras. We have been involved in this area for many years, beginning in the mid-80's with the demonstration that mutants in the CaaX box affected prenylation and palmitoylation of yeast Ras. Furthermore, we were the first to show that yeast and mammalian Ras proteins undergo carboxymethylation. Despite extensive characterization of protein prenylation and the development of farnesyltransferase inhibitors (FTIs) by big pharma, many questions remain. Perhaps the biggest gap in our knowledge was the failure to isolate the palmitoyl transferase for Ras, or for that matter, any of the numerous palmitoylated cellular proteins. In the last two years, our group succeeded in identifying the yeast Ras palmitoyltransferase (Ras PAT), initially by a genetic selection followed up by biochemical purification. The identification of the Ras PAT provided the handle necessary to identify putative PATs in yeast, flies, worms, mouse, and human. Some of the potential human PAT genes have been linked to human diseases. For the foreseeable future, we plan to capitalize on our identification of the first PAT. We will continue to use yeast to address structure function issues and to establish enzyme-substrate pairs for the yeast ORFs. We will collaborate with labs involved with the characterization of mammalian PATs.
Genetic dissection of two-component regulators in yeast Recent characterization of the osmotic response pathway in S. cerevisiae has uncovered a complex pathway consisting of two signal transduction modules. Changes in osmotic balance are sensed by a sensor-kinase, Sln1p, which undergoes autophosphorylates a conserved histidine. That phosphoryl group is then transferred to a conserved aspartate in the Sln1 receiver domain, and then to a histidine in the phosphorelay molecule, Ypd1p and finally to an aspartate on the independent receiver domain of the response regulator, Ssk1p. The HOG1 MAP kinase pathway is kept in the inactive state under normal osmotic conditions by virtue of Sln1p and thus Ssk1p phosphorylation, since activation of the HOG1 MEK kinase requires a dephosphorylated form of Ssk1p. We are interested in this pathway for several reasons. First, little is known about how osmotic stress is sensed in any system and yeast affords a nice opportunity to uncover basic principles. Second, histidine kinases are an interesting subset of protein kinases that has been somewhat overlooked in favor of Tyr and Ser/Thr kinases. Finally, two component histidine protein kinases are potential antifungal drug targets. Currently, systemic fungal infections are difficult to treat because of drug toxicity and the increasing emergence of resistance to the small group of available antifungals. Therefore, a better understanding of the function of fungal histidine kinases and associated two component like proteins could lead to improved antifungal drugs with reduced lower toxicity. This project is a collaborative effort between my lab and Dr. Jan Fassler at the University of Iowa.
Selected Publications
"Modulation Of Yeast Sln1 Kinase Activity By The Ccw12 Cell Wall Protein." Narang, S.S., Malone, C.L., Deschenes, R.J. and Fassler, J.S. J. Biol. Chem. In Press (2007)
"Palmitoylation: policing protein stability and traffic." Linder, M.E. and Deschenes, R.J. Nat. Rev. Mol. Cell. Biol. 8:74-84. (2007)
"Purification and characterization of recombinant protein acyltransferases." Budde, C., Schoenfish, M.J., Linder, M.E. and Deschenes, Rj.J. Methods 40:143-150. (2006)
"Protein palmitoylation by a family of DHHC protein S-acyltransferases." Mitchell, D.A., Vasudevan, A., Linder, M.E., Deschenes, R.J. J. Lipid Res. 47:1118-1127. (2006)
"Plasma membrane localization of Ras requires class C Vps proteins and functional mitochondria in Saccharomyces cerevisiae." Wang, G., Deschenes, R.J. Mol. Cell Biol. 26:3243-3255. (2006)
"DHHC9 and GCP16 constitute a human protein fatty acyltransferase with specificity for H- and N-Ras." Swarthout, J.T., Lobo, S. Farh, L., Croke, M., Greentree, W.K., Deschenes, R.J., and Linder, M.E. J. Biol. Chem. 280: 31141-31148. (2005).
"Model organisms lead the way to protein palmitoyl-transferases." Linder, M.E. and Deschenes, R.J. J. Cell Sci. 117: 521-526 (2004).
"Ypd1p, a Saccharomyces cerevisiae Histidine Phosphotransferase, shuttles between the nucleus and cytoplasm for SLN1-dependent phosphorylation of Ssk1p and Skn7p." Lu, M.-Y., Deschenes, R.J., and Fassler, J.S. Euc. Cell. 2: 1304-14 (2003).
"The eukaryotic two-component histidine kinase Sln1p regulates OCH1 via the transcription factor, Skn7p." Li, S., Dean, S., Li, Z., Horecka, J., Deschenes, R.J., and Fassler, J.S., (2002) Mol Biol Cell 13(2): 412-24 (2002).
"The cytoplasmic linker region of the Sln1 histidine kinase forms a coiled-coil important in regulation of kinase activity." Tao, W., Malone, C.L., Ault, A.D., Deschenes, R.J., Fassler, J.S. Mol. Micro. 43(2): 459-73 (2002).
"Palmitoylation and plasma membrane localization of Ras2p by a nonclassical trafficking pathway in Saccharomyces cerevisiae." Dong, X.,Mitchell, D.A., Lobo, S., Zhao, L., Bartels, D.J.,and Deschenes, R.J. Mol Cell Biol. Sep;23(18): 6574-84. (2003).
"New insights into the mechanisms of protein palmitoylation." Linder, M. and Deschenes, R.J. Biochemistry 42 (15): 4311-20 (2003).
"Erf4p and Erf2p Form an Endoplasmic Reticulum-associated Complex Involved in the Plasma Membrane Localization of Yeast Ras Proteins." Zhao, L., Lobo, S., Dong, X., Ault, A., and Deschenes, R.J. J.Biol. Chem. 277(51): 49352-9 (2002).
"Identification of a Ras palmitoyl acyl transferase in Saccharomyces cerevisiae." Lobo, S., Greentree, W.K., Linder, M.E., and Deschenes, R.J. J.Biol. Chem. 277(43): 41268-41273 (2002).