Undergraduate Degree: B.A., Biology,
Graduate Degree: Ph.D., Biology,
Fellowship: National Institutes of Health
Research InterestsThe major project in my laboratory is focused on elucidating the biological properties of TWEAK, a member of the TNF superfamily of structurally-related proteins that generally function as either apoptosis factors, immune system regulators, or pro-inflammatory cytokines. TWEAK is a multifunctional protein that can promote cell proliferation, migration, differentiation and pro-inflammatory molecule expression in vitro. It can also stimulate new blood vessel formation (angiogenesis) in vivo. TWEAK induces cellular responses via binding to a relatively small cell surface receptor named Fn14, a protein initially discovered in this laboratory by differential display cloning. TWEAK binding to this receptor activates the NF-kappaB, ERK and JNK signal transduction pathways. Our present research efforts can be categorized as follows:
a. Basic biology and structure/function analysis of the TWEAK-Fn14 system
b. Role of TWEAK in inflammation and angiogenesis
c. Role of the TWEAK-Fn14 system in tumor cell biology
Donohue, P.J., Richards, C.M., Brown, S.A.N., Hanscom, H.N., Buschman, J., Thangada, S., Hla, T., Williams, M.S. and Winkles, J.A. (2003). TWEAK is an endothelial cell growth and chemotactic factor that also potentiates FGF-2 and VEGF-A mitogenic activity. Arterioscler. Thromb. Vasc. Biol. 23:594-600.
Ho, D.H., Vu, H., Brown, S.A.N., Donohue, P.J., Hanscom, H.N. and Winkles, J.A. (2004). Soluble TWEAK overexpression in HEK293 cells promotes tumor growth and angiogenesis in athymic nude mice. Cancer Res. 64:8968-8972.
Tran, N.L., McDonough, W.S., Savitch, B.A., Fortin, S.P., Winkles, J.A., Symons, M., Nakada, M., Cunliffe, H.E., Hostetter, G., Hoelzinger, D.B., Rennert, J.L., Michaelson, J.S., Burkly, L.C., Lipinski, C.A., Loftus, J.C., Mariani, L. and Berens, M.E. (2006). Increased Fn14 expression levels promote glioma cell invasion via Rac1 and NF-kappaB and correlate with poor patient outcome. Cancer Res. 66:9535-9542.
Willis, A.L., Tran, N.L., Chatigny, J.M., Charlton, N., Vu, H., Brown, S.A.N., Black, M.A., McDonough, W.S., Fortin, S.P., Niska, J.R., Winkles, J.A. and Cunliffe, H.E. (2008). The Fn14 receptor is highly expressed in HER2-positive breast tumors and regulates breast cancer cell invasive capacity. Mol. Cancer Res. 6:725-734.
Winkles, J.A. (2008). The TWEAK-Fn14 cytokine-receptor axis: Discovery, biology, and therapeutic targeting. Nature Reviews Drug Discovery 7:411-425.
Brown, S.A.N., Ghosh, A. and Winkles, J.A (2010). Full-length, membrane-anchored TWEAK can function as a juxtacrine signaling molecule and activate the NF-kB pathway. J. Biol. Chem. 285:17432-17441.
Zhou, H., Marks, J.W., Hittelman, W.N., Yagita, H., Rosenblum, M.G. and Winkles, J.A. (2011). Development and characterization of a potent immunotoxin targeting the Fn14 receptor on solid tumor cells. Mol. Cancer Ther. 10:1276-1288.