Bingcheng Wang, Ph.D.
Associate Professor of Pharmacology and Oncology
Rammelkamp Center for Research, R421
MetroHealth Medical Center
School of Medicine
Case Western Reserve University
2500 MetroHealth Drive
Cleveland, OH 44109
Phone: (216) 778-4256
Fax: (216) 778-4321
E-mail: bxw14@case.edu
Research
Primary interests of my laboratory are the molecular mechanisms governing tumor metastasis, a frequently fatal phase of tumor progression in cancer patients. There are two key steps in tumor metastasis. One is tumor cell dissemination to a distal organ; the other is metastatic tumor cell growth at the distal site. Cell motility plays a critical role in tumor cell dissemination. Metastatic tumor cell growth at distal sites is regulated by paracrine and autocrine factors, many of which converge on the Ras/Raf/MEK/ERK1/2 MAP kinase (MAPK) growth-stimulatory signaling pathway. Therefore, agents that can suppress either cell motility or MAPK activity can be exploited to prevent and/or treat metastasis. Agents that can accomplish both feats will be even more desirable. We have found that agonists (or activators) of EphA kinases, including EphA1 and EphA2, possess this unique combination of properties, i.e., they are capable of both inhibiting cell motility and suppressing Ras/MAPK cascade. Moreover, increased expression or mutation of EphA kinases has been documented in breast, prostate and colon cancer cells but not in their normal counterparts, suggesting that EphA kinases represent attractive targets in cancer intervention.
Current research covers four related areas. 1) To characterize novel signal pathways initiated by EphA kinases that inhibit cell motility and Ras/MAPK cascade using contemporary molecular, cellular, genomic and proteomic approaches. 2) To establish the role of EphA overexpression in breast and prostate cancer progression using athymic mouse model system. 3) To investigate the structure/function relationship of Eph kinase and ephrin-ligand interactions. 4) To isolate and characterize new and more potent agonists of Eph kinases as novel therapeutics to prevent and/or treat tumor metastasis. In addition, we are searching for small compounds that can bind and modulate Eph kinase function through virtual screening using super computers. Candidate compounds are then tested in vitro and in vivo for anti-cancer activities. 5) To investigate how Eph/ephrin interactions may regulate epithelial morphogenesis, a fundamental developmental process that gives rise to many epithelial organs such as breast, lung, kidney and prostate. Understanding molecular mechanisms of epithelial morphogenesis can yield novel insight on cancer development.
SELECTED REFERENCES:
Wang, B., Zhang, L., Liu, Y.-C., Jelinek, T., Ruoslahti, E., and Fu, H. (1999). Isolation of high affinity antagonists of 14-3-3 proteins by phage display. Biochemistry 38:12499-12504.
Wang, B., Zou, J. X., Bek-Rylander, B., and Ruoslahti, E. (2000). R-Ras contains a proline-rich site that binds to Nck and is required for integrin activation by R-Ras. Journal of Biological Chemistry 275:5222-5228.
Miao, H., Burnett, E., Kinch, M. S., Simon, E., and Wang, B. (2000). EphA2 kinase activation suppresses integrin function and causes focal adhesion kinase dephosphorylation. Nature Cell Biology 2:62-69.
Miao, H., Wei, B.-R., Peehl, D. M., Li, Q., Burnett, E., Alexandrou, T., Sedor, J. R., Schelling, J. R., and Wang B. (2001). EphA kinase activation inhibits Ras/MAPK pathway. Nature Cell Biology 3:527-530.
Myshkin, E. and Wang, B. (2003). Chemometrical classification of ephrin ligands and Eph kinases using GRID/CPCA approach. Journal of Chemical Information and Computer Sciences 43:1004-1010.