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Biological Sciences Department Faculty
Deborah Chadee, PhD.
Postdoctoral Research Fellow, Massachusetts General Hospital and Tufts Medical Center
Ph.D. University of Manitoba, Canada 1999
Research in my lab is focused on mitogen-activated protein kinase (MAPK) signaling. Eukaryotic cells have conserved MAPK signaling pathways that respond to diverse extracellular stimuli and regulate a wide range of biological responses. We are investigating how MAPK signaling pathways are activated by various stimuli, and how altered regulation of MAPK signaling affects cellular processes such as proliferation, differentiation and apoptosis.
The MAPKs are organized in a three-tiered kinase signaling module, where a MAPK kinase kinase (MAP3K) phosphorylates and activates a MAPK kinase (MAP2K) which in turn, phosphorylates and activates a MAPK. Our studies thus far have been focused on the MAP3K, mixed-lineage kinase 3 (MLK3), which is a member of a family of serine/threonine protein kinases that activate multiple MAPK pathways.
One major focus of our research is defining the biological role of MLK3 and other MAP3Ks in cell proliferation and cancer. We previously found that MLK3 plays an important role in mitogen activation of B-Raf, ERK and cell proliferation. In addition, we found that MLK3 interacts with Merlin, the protein encoded by the Neurofibromatosis Type 2 (NF2) tumor suppressor gene. Merlin inhibits MLK3 activity, and NF2 tumor cells that lack functional Merlin have elevated MLK3 activity. Furthermore, we observed that Merlin blocks the interaction between MLK3 and Cdc42, an upstream activator of MLK3. Future studies will be focused on elucidating the role of MLK3 in Merlin-mediated growth suppression.
Another major research interest is to decipher the biochemical regulation of MLK3 by growth factor and cytokine signaling pathways. Tumor necrosis factor (TNF) activates MLK3, which in turn activates JNK MAPK signaling. We have observed that the TNF receptor-associated factors, TRAF2 and TRAF6, associate with MLK3 and are required for full activation of MLK3 by TNF. Further studies will be focused on determining the mechanisms by which MLK3 is activated by other pro-inflammatory cytokines and stressful stimuli.
Involvement of mixed lineage kinase 3 in cancer. Chadee DN. Can J Physiol Pharmacol. 2013 Apr;91(4):268-74. doi: 10.1139/cjpp-2012-0258. Epub 2012 Dec 19. Review.
Zhan, Y., Abi Saab, W.F., Modi, N., Stewart, A.M., Liu, J., and Chadee, D.N. (2012) Mixed lineage kinase 3 is required for matrix metalloproteinase expression and invasion in ovarian cancer cells. Exp Cell Res. 318, 1641-1648.
Abi Saab, W.F., Brown, M.S., and Chadee, D.N. (2012) MLK4β functions as a negative regulator of MAPK signaling and cell invasion. Oncogenesis. 1, 1-6.
Zhan, Y., Modi, N., Stewart, A.M., Hieronimus, R.L., Liu, J., Gutmann, D.H. and Chadee, D.N. (2011) Regulation of mixed lineage kinase 3 is required for neurofibromatosis-2-mediated growth suppression in human cancer. Oncogene, 30(7):781-9.
Zhan, Y. and Chadee D.N. (2010) Inhibition of Cdc42-mediated activation of mixed lineage kinase 3 by the tumor suppressor protein merlin. Small GTPases, Extra View, 1(3):183-6.
Chadee D.N. and Kyriakis, J.M. (2010) Activation of SAPK/JNKs in vitro. Methods Mol Biol., 661:59-73.
Cole, E.T., Zhan, Y., Abi Saab, W.F., Korchnak, A., Ashburner, B.P., and Chadee, D.N. (2009) Mixed lineage kinase 3 negatively regulates IKK activity and enhances etoposide-induced cell death.Biochimica et Biophysica Acta- Molecular Cell Research. Dec;1793 (12):1811-8.
Korchnak, A.C., Zhan, Y., Aguilar, M.T., and Chadee, D.N. (2009) Cytokine-induced activation of mixed lineage kinase 3 requires TRAF2 and TRAF6. Cell Signal. Nov; 21(11):1620-5.
Kosik A., Bekier M.E., Katusin J.D., Kaur, H., Zhou, X., Diakonova, M., Chadee, D.N. and Taylor, W.R. (2009) Investigating the role of Aurora kinases in RAS signaling. J. Cell. Biochem. Jan 1;106(1):33-41.
Chadee, D.N., Xu, D., Hung, G., Andalibi, A., Lim, D.J., Luo, Z., Gutmann, D.H., and Kyriakis, J.M. (2006) MLK3 regulates B-Raf through a mechanism that involves maintenance of the B-Raf/Raf-1 complex and inhibition by the NF2 tumor suppressor protein. Proc. Natl. Acad. Sci. U S A. Mar 21;103(12), 4463-8.
Chadee, D.N., and Kyriakis, J.M. (2004) A novel role for MLK3 in B-Raf activation and cell proliferation. Cell Cycle, 3(10), 1227-29
Chadee, D.N., and Kyriakis, J.M. (2004) MLK3 is required for mitogen activation of B-Raf, ERK, and cell proliferation. Nat. Cell Biol., 6(8), 770-6.
Kyriakis, J.M., Liu, H., and Chadee, D.N. (2004) Activation of SAPKs/JNKs and p38s in vitro. Methods Mol. Biol., 250, 61-88.
Chadee, D.N., Yuasa, T., and Kyriakis, J.M. (2002) Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste-20p homologue GCK and the adapter protein TRAF2. Mol. Cell. Biol., 22, 737-749.
Chadee, D.N., Peltier, C.P., and Davie, J.R. (2002) Histone H1(S)-3 phosphorylation in Ha-ras oncogene-transformed mouse fibroblasts. Oncogene, 21(55), 8397-403.
Chadee, D.N., Hendzel, M.J., Tylipski, C.P., Allis, C.D., Bazett-Jones, D.P., Wright, J.A., and Davie, J.R. (1999) Increased Ser-10 phosphorylation of histone H3 in oncogene-transformed and mitogen-stimulated mouse fibroblasts. J. Biol. Chem., 274, 24914-20.
Davie, J.R., and Chadee, D.N. (1998) Regulation and regulatory parameters of histone modifications. J. Cell. Biochem., 30/31, 203-213.
Chadee, D.N., Allis C.D., Wright, J.A., and Davie. J.R. (1997) Histone H1b phosphorylation is dependent upon ongoing transcription and replication in normal and ras-transformed mouse fibroblasts. J. Biol. Chem., 272, 8113-8116.
Chadee, D.N., Taylor, W.R., Hurta, R.A., Allis, C.D., Wright, J.A., and Davie, J.R. (1995) Increased phosphorylation of histone H1 in mouse fibroblasts transformed with oncogenes or constitutively active MAP kinase kinase. J. Biol. Chem.,270, 20098-20105.