EGF-like Growth Factors

We are interested in uncovering the physiological roles of growth factors in the epidermal growth factor (EGF) family. EGF-like growth factors, such as EGF and transforming growth factor-α (TGF-α), are well known as autocrine signaling molecules in cancer, development and wound healing. Other members of this family, which like EGF and TGF-α serve as ligands for the ErbB class of receptor tyrosine kinases, have not been studied as extensively and their functions are less well defined. We have been examining the regulation and function of heparin-binding EGF-like growth factor (HB-EGF) in several contexts, including prostate and bladder cancer and in hypertrophic muscle growth. Our studies have indicated that HB-EGF, and a structurally related growth factor, amphiregulin, are likely to be important in cell-to-cell signaling in these systems and that their diverse biological activities may be dependent on distinct forms of the proteins.

Selected Publications

Freeman, M.R., Yoo, J.J., Raab, G., Soker, S., Schneck, F.X., Renshaw, A., Klagsbrun, M., and Atala, A. (1997) Heparin-binding EGF-like growth factor is an autocrine growth factor for human urothelial cells and is synthesized by epithelial and smooth muscle cells in the human bladder. Journal of Clinical Investigation 99:1028-1036.

Park, J.M., Adam, R.M., Peters, C.A., Guthrie, P.D., Sun, Z., Klagsbrun, M., and Freeman, M.R. (1999) AP-1 mediates stretch-induced expression of heparin-binding EGF-like growth factor in bladder smooth muscle cells. American Journal of Physiology (Cell Physiol.) C294-301.

Adam, R.M., Borer, J.G., Williams, B.J., Eastham, J.A., Loughlin, K.R., Freeman, M.R. (1999) Amphiregulin is coordinately expressed with heparin-binding epidermal growth factor-like growth factor in the interstitial smooth muscle of the human prostate. Endocrinology 140:5866-5875.

Lin, J., Hutchinson, L., Gaston, S.M., Raab, G., and Freeman, M.R. (2001) BAG-1 is a novel cytoplasmic binding partner of the membrane form of heparin-binding EGF-like growth factor: A unique role for proHB-EGF in cell survival regulation. Journal of Biological Chemistry 276:30127-30132.

Adam, R.M., Kim, J., Lin, J., Orsola, A., Rice, D.C., and Freeman, M.R. (2002) Heparin-binding EGF-like growth factor stimulates androgen-independent prostate tumor growth and antagonizes androgen receptor function. Endocrinology 143:4599-4608.

Adam, R.M., Danciu, T., McClellan, D.L., Borer, J.G., Lin, J., Zurakowski, D., Weinstein, M.H., Rajjayabun, P., Mellon, J.K., and Freeman, M.R. (2003) A nuclear form of the heparin-binding EGF-like growth factor precursor is a feature of aggressive transitional cell carcinoma. Cancer Research 63:484-490.

Kim, J., Lin, J., Adam, R.M., Lamb, C., Shively, S.B., and Freeman, M.R. (2005) An oxidative stress mechanism mediates chelerythrine-induced heparin-binding EGF-like growth factor ectodomain shedding. Journal of Cellular Biochemistry 94:39-49.

Kim, J., Adam, R.M., and Freeman, M.R. (2005) Trafficking of nuclear HB-EGF into an epidermal growth factor receptor-dependent autocrine loop in response to oxidative stress. Cancer Research 65:8242-8249.