ResearchThe 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. TWEAK binding to this receptor activates several signaling pathways, including the NF-kappaB, ERK and Akt pathways. Our present research efforts can be categorized as follows:
a. Basic biology and structure/function analysis of the TWEAK-Fn14 axis
b. Role of TWEAK in inflammation and angiogenesis
c. Role of the TWEAK-Fn14 axis in tumor cell migration and invasion
Publications
- Wiley, S.R., Cassiano, L., Lofton, T., Davis-Smith, T., Winkles, J.A., Lindner, V., Liu, H., Daniel, T.O., Smith, C.A. and Fanslow, W.C. (2001). A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity 15:837-846.
- Tran, N.L., McDonough, W.S., Donohue, P.J., Winkles, J.A., Berens, T.J., Ross, K.R., Hoelzinger, D.B., Beaudry, C., Coons, S.W. and Berens, M.E. (2003). The human Fn14 receptor gene is up-regulated in migrating glioma cells in vitro and overexpressed in advanced glial tumors. Am. J. Path. 162:1313-1321.
- 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.
- Brown, S.A.N., Richards, C.M., Hanscom, H.N., Feng, S.Y. and Winkles, J.A. (2003). The Fn14 cytoplasmic tail binds tumor necrosis factor receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappaB activation. Biochem. J. 371:395-403.
- 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.
Brown, S.A.N., Hanscom, H.N., Vu, H., Brew, S.A. and Winkles, J.A. (2006). TWEAK binding to the Fn14 cysteine-rich domain depends on charged residues located in both the A1 and D2 modules. Biochem. J. 397:297-304.
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. Personal HistoryUndergraduate Degree: B.A., Biology, University of Delaware
Graduate Degree: Ph.D., Biology, University of Virginia
Fellowship: National Institutes of Health
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