Metalloprotease-disintegrins (ADAMs): key players in growth factor signaling, angiogenesis and arthritis
Studies in my lab are focused on a family of membrane-anchored metalloproteases named ADAMs (a disintegrin and metalloprotease) with an emphasis on their role in tissue degeneration and regeneration, rheumatoid arthritis and angiogenesis. ADAMs are membrane-anchored glycoproteins that can function as molecular signaling switches by cleaving and releasing other membrane proteins from cells. This process, which is referred to as “protein ectodomain shedding”, can activate or inactivate the substrate protein, or substantially change its functional properties. Examples of membrane proteins whose function is regulated by ADAMs are the pro-inflammatory cytokine TNF alpha, the main target of drugs for treatment of rheumatoid arthritis, and several ligands of the epidermal growth factor receptor (EGFR), a receptor with important roles in development, cancer and wound healing.
We are taking three complementary approaches to study the function of ADAMs and their role in ectodomain shedding. The first is to create and analyze mice lacking specific ADAMs (“knockout mice”), which are essential for evaluating the function of these proteins during development and in mouse models for human diseases. The second is to use cells from these knockout mice to uncover the molecular mechanism underlying the function of different ADAMs, for example by identifying defects in ectodomain shedding in cells that lack one or more ADAMs. The third is to biochemically characterize recombinant ADAMs and determine their substrate specificity and inhibitor profile. Results obtained from studies in vitro can be extended and verified in vivo in cell culture and whole animals, and vice versa.
Currently the lab is focused on understanding how ADAMs regulate the activity of ligands of the epidermal growth factor receptor (EGFR), on elucidating the mechanism underlying the recently discovered roles of ADAMs in angiogenesis, and on their involvement in rheumatoid arthritis and healing of bone fractures and skin wounds. We anticipate that our studies will provide interesting new insights into the role of these proteins in cell-cell interactions and signaling and hope that they will help devise new approaches to fighting autoimmune disease and tissue degeneration and to stimulating tissue growth and regeneration.
L Peduto, L., Reuter, V.E., Sehara-Fujisawa, A., Shaffer, D.R., Scher, H.I., and Blobel, C.P. 2006. ADAM12 is highly expressed in carcinoma-associated stroma and is required for mouse prostate tumor progression. Oncogene 25, 5462-5466.
Weskamp, Gisela, Ford, Jill W, Sturgill, Jamie, Martin, Steve, Docherty, Andrew J P, Swendeman, Steven, Broadway, Neil, Hartmann, Dieter, Saftig, Paul, Umland, Shelby, Sehara-Fujisawa, Atsuko , Black, Roy A, Ludwig, Andreas, Becherer, J David, Conrad, Daniel H and Blobel, Carl P. 2006. ADAM10 is a principal 'sheddase' of the low-affinity immunoglobulin E receptor CD23. Nature Immunology 7, 1293 - 1298.
Horiuchi, Keisuke, Le Gall, Sylvain, Schulte, Marc, Yamaguchi, Takafumi, Reiss, Karina , Murphy, Gillian, Toyama, Yoshiaki , Hartmann, Dieter, Saftig, Paul and Blobel, Carl P. 2007. Substrate Selectivity of Epidermal Growth Factor-Receptor Ligand Sheddases and their Regulation by Phorbol Esters and Calcium Influx. Molecular Biology of the Cell 18, 176-188.
Blobel, C.P. 2005. ADAMs: key components in EGFR signaling and development Nature Reviews in Molecular and Cellular Biology 6:32-43
Zhou, H., Weskamp, G., Sahin, U., Chesneau, V., Chiusaroli, R., Hahn, R., Wilkes, D., Fisher, P., Baron, R., Manova, K., Basson, C.T., Hempstead, B., and Blobel, C.P. 2004. Essential role for ADAM19 in cardiovascular morphogenesis. Mol. Cell Biol. , 24:96-104.
Sahin, U., Weskamp, G., Zhou, H., Higashiyama, S., Peschon, J., Hartmann, D., Saftig, P., and Blobel, C.P. Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR-ligands. 2004. J. Cell Biol., 164:769-779.
Zheng, Y., Saftig, P., Hartmann, D., Blobel, C.P. Evaluation of the contribution of different ADAMs to TNF alpha shedding and of the function of the TNF alpha ectodomain in ensuring selective stimulated shedding by the TNF alpha convertase (TACE/ADAM17). 2004. J. Biol. Chem. 279:42898-42906.
Horiuchi, K., Weskamp. G., Lum, L., Hammes, H.-P., Cai, H., Brodie, T.A., Ludwig, T., Chiusaroli, R., Baron, R., Preissner, K.T., Manova, K., and Blobel, C.P. 2003. Potential role for ADAM15 in pathological neovascularization in mice. Mol. Cell Biol. 23:5614-5624.
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