Roy J. Duhè, Ph.D.
Associate Professor
Research 406
(601) 984-1625
RDuhe@pharmacology.umsmed.edu
Current Research
Our laboratory conducts research on the fundamental mechanisms regulating Janus kinase (JAK) activity, and on the role of dysregulated JAK activity in human diseases such as cancers. Janus protein tyrosine kinases are essential early mediators of cytokine-initiated signal transduction. Dysregulation can arise from defects in any one of the multiple mechanisms that control the catalytic state of JAKs. Examples of human diseases associated with dysregulated JAK2 include polycythemia vera and other myeloproliferative disorders (JAK2(V617F) mutant), Hodgkin lymphoma (jak2 gene amplification), atypical forms of chronic myelogenous leukemia (TEL/JAK2 chimera), and hepatocellular carcinoma (due to hypermethylational silencing of SOCS-1, a negative feedback modulator of JAK2).
We are currently studying three specific regulatory mechanisms. One mechanism involves tyrosine phosphorylation within the "activation loop" of the catalytic domain; we have shown that this mechanism dramatically alters the enzyme's efficiency with respect to ATP (Chatti, et. al., 2004). A second mechanism involves the autoregulatory domain outside of the JAK2 catalytic domain. The third mechanism of JAK regulation involves the redox state of the enzyme. JAK2 and JAK3 are maximally active under mildly reducing conditions and completely inactive under mildly oxidizing conditions; the biochemical reversibility of these activity states are consistent with an intramolecular thiol-disulfide bond exchange. We have identified four cysteine residues in JAK2 that are critical for this phenomenon (Mamoon, et. al., submitted for publication).
The ultimate goals of our research are to 1) better define the pathogenic consequences of dysregulated JAK activity and 2) to provide a rational mechanistic basis for the design of novel JAK-targeted chemotherapy.
Selected Publications
Naila M. Mamoon*, John K. Smith*, Kiranam Chatti, Sheeyong Lee, Kanakadurga Kundrapu, and Roy J. Duhè “Multiple cysteine residues are implicated in JAK2-mediated catalysis", (2007) Biochemistry (e-publication ahead of print) 
(e-publication ahead of print)
Sheeyong Lee and Roy J. Duhè, "Kinase activity and subcellular distribution of a chimeric green fluorescent protein-tagged Janus kinase 2." (2006) Journal of Biomedical Science 13: 773-786.
John K. Smith, Naila M. Mamoon and Roy J. Duhè, "Emerging roles of targeted small colecule protein-tyrosine kinase inhibitors in cancer therapy." (2004) Oncology Research 14: 175-225.
Kiranam Chatti, William L. Farrar and Roy J. Duhè, "Tyrosine phosphorylation of the Janus Kinase 2 activation loop is essential for a high-activity catalytic state but dispensable for a basal catalytic state", (2004) Biochemistry 43: 4272-4283.
Viktoria Lukashova, Zhangguo, Chen, Roy J. Duhè, Marek Rola-Pleszcynski, and Jana Stankova "Janus kinase 2 activation by the platelet-activating factor receptor (PAFR): roles of Tyk2 and PAFR C terminus ", (2003) Journal of Immunology 14: 175-222.
Roy J. Duhè, Emily Ann Clark and William L. Farrar, "Characterization of the in vitro kinase activity of a partially purified soluble GST/JAK2 fusion protein" (2002) Molecular and Cellular Biochemistry 236: 23-35.
Roy J. Duhè, Li-Hua Wang and William L. Farrar, "Negative Regulation of Janus Kinases" (2001) Cell Biochemistry & Biophysics 34: 17-59.
Links of Interest
CANCER INFORMATION
Jackson Cancer Research Interest Group (J-CRIG)
http://jcrig.umc.edu/
National Cancer Institute CancerNet
http://cancernet.nci.nih.gov/
National Cancer Institute - Frederick Cancer Research and DevelopmentCenter
http://web.ncifcrf.gov/
American Cancer Society
http://www.cancer.org/
Association of American Cancer Institutes (find your nearest cancer institute)
http://www.aaci-cancer.org/
BIO-SCIENCE DATABASES
The National Center for Biotechnology Information (GenBank, PUBMEDand more)
http://www.ncbi.nlm.nih.gov/
Cytokines Online Pathfinder Encyclopaedia
http://www.copewithcytokines.de/cope.cgi
Protein Kinase Resource
http://www.sdsc.edu/kinases/
The Nitric Oxide Homepage
http://www.apnet.com/no/jussayno.htm
OTHER HEALTH & MEDICAL INFORMATION
The Centers for Disease Control
http://www.cdc.gov/
National Institute of Allergy and Infectious Diseases, Division of Acquired Immunodeficiency Syndrome
http://www.niaid.nih.gov/daids/default.htm
U.S. Food and Drug Administration
http://www.fda.gov/default.htm