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Research Focus

Our lab is studying the role of intracellular signaling pathways in mammalian tumorigenesis and in other cellular functions. The big mitogen-activated protein kinase 1 (BMK1) pathway is the most recently discovered and least-studied mammalian mitogen-activated protein (MAP) kinase cascade. In order to study the function of this MAP kinase in animals, we produced condition knockout mouse of BMK1/ERK5. We discovered that BMK1 is involved in tumor cell proliferation, tumor-associated angiogenesis as well as tumor metastasis. Most recently, we generated small molecular inhibitor of BMK1/ERK5 for the cancerous BMK1 signaling pathway. We found that this pharmacological BMK1 inhibitor significantly suppresses tumor growth and neovascularization in animal cancer models and importantly, the BMK1 inhibitor is well tolerated in animal. As BMK1 is expressed in most tumor cells, our results suggest that cancer therapies targeting BMK1 may be useful for treating diverse types of human tumors. Our long-term goal is to contribute to the understanding of the molecular action of signaling pathways in cancer development and to provide critical knowledge for advancing the development of cancer therapy targeting these signaling pathways.

Education

B.S., Chemistry, National Taiwan University, 1980
Ph.D., Molecular Biology, Michigan State University, 1989

Awards & Professional Activities

DuVall award recipient, Michigan State University
American Heart Association Fellow
Department of Defense, Prostate Cancer Research Program Idea Award
Department of Defense, Breast Cancer Concept Award
Department of Defense, Breast Cancer Research Program Idea Award
California Tobacco-Related Disease Research Program Award (2006)
California Tobacco-Related Disease Research Program Award (2010)

Selected References

1. Lee, J.-D., Ulevitch, R.J. and Han, J.H. Primary structure of BMK-1; A new mammalian MAP kinase. Biochem. Biophys. Res. Comm. 213:715-724, 1995.

2. Abe, J., Kusuhara,M., Ulevitch, R.J., Berk, B.C. and Lee, J.-D. Big MAP kinase 1 (BMK1) is a redox sensitive kinase. J. Biol. Chem. 271:16586-16590, 1996.

3. Kato,Y., V.V.Kravchenko, R.I.Tapping, J.Han, R.J.Ulevitch, and J.-D.Lee. BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J. 16: 7054, 1997.

4. Kato,Y., R.I.Tapping, S.Huang, M.H.Watson, R.J.Ulevitch, and J.D.Lee. Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Nature 395: 713, 1998.

5. Chao, T.-H., Hayashi, M., Tapping, R.I., Kato, Y., and Lee J.-D. MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway. J. Biol. Chem. 274:36035-36038, 1999.

6. Kato Y, Zhao M, Morikawa A, Sugiyama T, Chakravortty D, Koide N, Yoshida T, Tapping RI, Yang Y, Yokochi T, Lee J-D. Big mitogen-activated kinase regulates multiple members of the MEF2 protein family. J. Biol. Chem. 275:18534-18540, 2000.

7. Kato Y, Chao T-H, Hayashi M, Tapping RI, Lee J.-D. Role of BMK1 in regulation of growth factor-induced cellular responses. Immunologic Res. 3:233-237, 2000.

8. Hayashi,M., R.I.Tapping, T.H.Chao, J.F.Lo, C.C.King, Y.Yang, and Lee, J.-D., BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase. J. Biol. Chem. 276: 8631-8634. 2001.

9. Kim, S.-W., Hayashi, M., Lo, J.-F., Yang, Y., Yoo, J.-Y., Lee, J.-D. ARF4 small GTPase mediates EGFR-dependent PLD2 activation. J. Biol. Chem. 278:2661-2668. 2003.

10. Hayashi, M., S. W. Kim, K. Imanaka-Yoshida, T. Yoshida, E. D. Abel, B. Eliceiri, Y. Yang, R. J. Ulevitch, and Lee, J. D., Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure. J.Clin.Invest 113:1138, 2004.

11. Lo, J. F., M. Hayashi, S. W. Kim, B. Tian, J. F. Huang, C. Fearns, S. Takayama, J. M. Zapata, Y. Yang, and Lee, J.-D., Tid1, a cochaperone of the heat shock 70 protein and the mammalian counterpart of the Drosophila tumor suppressor l(2)tid, is critical for early embryonic development and cell survival. Mol.Cell Biol. 24:2226. 2004.

12. Kim, S. W., Chao, T.-H., Xiang, R., Lo, J.-F., Campbell, M. J., Fearns, C. and Lee, J.-D., Tid1, the human homologure of a Drosophila tumor suppressor, reduces the malignant activity of erbB-2 incarcinoma cells. Cancer Research 64(21): 7732, 2004.

13. Hayashi, M and Lee, J.-D. Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice. J. of Molecular Medicine, Dec; 82(12): 7732, 2004.

14. Tapping, R. I., Yutaka, K., Chao, T. H., Hayashi, M., Lo, J. F., Kim, S. W., and Lee, J. D. Investigating the Cellular BMK1/ERK5 Signaling Pathway. Methods Mol.Biol., 250: 89-96, 2004.

15. Hayashi, M., Fearns, C., Eliceiri, B., Yang, Y., and Lee, J.-D. BMK1/ERK5 signaling pathway is essential for tumor-associated angiogenesis. Cancer Res. 65:7699, 2005.

16. Kim, S. W., M. Hayashi, J. F. Lo, C. Fearns, R. Xiang, G. Lazennec, Y. Yang, and Lee, J.-D. Tid1 negatively regulates the migratory potential of cancer cells by inhibiting the production of interleukin-8. Cancer Res. 65:8784, 2005.

17. Lo, J.F., Zhou, H., Fearns, C., Reisfeld, R. A., Yang, Y., Lee, J.-D., Tid1 is required for T cell transition from double-negative 3 to double-positive stages. J Immunol. 2005 May 15;174(10):6105-12, 2005.

18. Hayashi, M., Imanaka-Yoshida, K., Yoshida, T., Wood, M., Fearns, C., Tatake, R. J., Lee, J.-D., A critical role of mitochondrial HSP40 in preventing dilated cardiomyopathy, Nature Medicine, 12(1):128-132, 2006.

19. Zhu, J.-H., Chen, R., Yi, W., Cantin, G. T., Fearns, C., Yang, Y., Yates, J. R., and Lee, J.-D. Protein tyrosine phosphatase PTPN13 negatively regulates Her2/ErbB2 malignant signaling. Oncogene. 2008 Apr 17;27(18):2525-31, 2008.

20. Cantin, G.T., Yi, W., Lu, B., ParK, S., Xu, T., Lee, J.-D.*, and Yates, J.R.*, Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis. J Proteome Research. 7(3):1346-51, 2008.

21. Chen, R.-Q., Yang, Q.-K., Lu, B.-W., Wei, Y., Cantin, G.T., Chen, Y.-L., Fearns, C., Yates, J. R. III and Lee, J.-D., CDC25B mediates rapamycin-induced oncogenic responses in cancer cells. Cancer Res. 69(6):2663-8, 2009.

22. Chen, Y., Lu, B., Yang, Q., Fearns, C., Yates, J. R., III, and Lee, J.-D. Combined Integrin Phosphoproteomic Analyses and siRNA-based Functional Screening Identified Key Regulators for Cancer Cell Adhesion and Migration. Cancer Res. 69(8):3713-20, 2009.

23. Chen, R.-Q., Yang, Q.-K., Chen, Y.-L., Oliveira, V. A., Dalton, W. S., Fearns, C. and Lee, J.-D. Kinome siRNA screen identifies SMG-1 as a negative regulator of hypoxia-inducible factor-1alpha in hypoxia. J Biol Chem. 284(25):16752-8, 2009.

24. Yang,Q., Deng,X., Lu,B., Cameron,M., Fearns,C., Patricelli,M.P., Yates,J.R., III, Gray,N.S., and Lee,J.-D. Pharmacological inhibition of BMK1 suppresses tumor growth through promyelocytic leukemia protein. Cancer Cell 18:258-267. 2010.

25. Deng,X.,Yang, Q., Kwiatkowski, N., Sim, T., McDermott, U., Settleman, J., Lee, J.-D., Gray, N. S. Discovery of a 2-amino-5,11-dimethyl-5H-benzo[e]pyrimido-[5,4-b][1,4]diazepin-6(11H)-one as a Potent and Selective Inhibitor of Big MAP Kinase 1 (BMK1/ERK5). ACS Med Chem Lett. 2011 Mar 10;2(3):195-200. 

26. Yang, Q., Lee, J.-D. Targeting the BMK1 MAP Kinase Pathway in Cancer Therapy. Clin Cancer Res. 2011 Jun 1;17(11):3527-32. 

27. Deng, X., Dzamko, N., Prescott, A., Davies, P., Liu, Q., Yang, Q., Lee, J.-D., Patricelli, M. P., Nomanbhoy, T. K., Alessi, D. R. Gray, N. S., Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nat Chem Biol. 2011 Apr;7(4):203-5. 

28. Miduturu, C.V., Deng, X., Kwiatkowski, N., Yang, W., Brault, L., Filippakopoulos, P., Chung, E., Yang, Q., Schwaller, J., Knapp, S., King, R.W., Lee, J.-D., Herrgard, S., Zarrinkar, P., Gray, N.-S., High-throughput kinase profiling: a more efficient approach toward the discovery of new kinase inhibitors.Chem Biol. 2011 Jul 29;18(7):868-79.

29. Patricelli, M.P., Nomanbhoy, T.K., Wu, J., Brown, H., Zhou, D., Zhang, J., Jagannathan, S., Aban, A., Okerberg, E., Herring, C., Nordin, B., Weissig, H., Yang, Q., Lee, J.-D., Gray, N.S., Kozarich, J.W., In situ kinase profiling reveals functionally relevant properties of native kinases.Chem Biol. 2011 Jun 24;18(6):699-710.

30. Chen, R., Yang, Q., Lee, J.-D., BMK1 kinase suppresses epithelial-mesenchymal transition through the Akt/GSK3ss signaling pathway. Cancer Res. 2012 Jan 26. [Epub ahead of print]