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Published 1 March 2004. doi:10.1083/jcb.200307137
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 5, 769-779
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Article

 Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands

Umut Sahin1,2, Gisela Weskamp1, Kristine Kelly1,3, Hong-Ming Zhou1, Shigeki Higashiyama4, Jacques Peschon5, Dieter Hartmann6, Paul Saftig7, and Carl P. Blobel1

1 Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
2 Department of Molecular and Cellular Biology and Biochemistry, Brown University, Providence, RI 02912
3 Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021
4 Department of Medical Biochemistry, Ehime University School of Medicine, Ehime 791-0301, Japan
5 Amgen Inc., Seattle, WA 98101
6 Department for Human Genetics, K.U. Leuven and Flanders Interuniversity Institute for Biotechnology (VIB-4), 3000 Leuven, Belgium
7 Biochemical Institute, Christian-Albrechts University, D-24098 Kiel, Germany

Address correspondence to Carl P. Blobel, Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, Box 368, 1275 York Avenue, New York, NY 10021. Tel.: (212) 639-2915. Fax: (212) 717-3047. email: c-blobel{at}ski.mskcc.org

All ligands of the epidermal growth factor receptor (EGFR), which has important roles in development and disease, are released from the membrane by proteases. In several instances, ectodomain release is critical for activation of EGFR ligands, highlighting the importance of identifying EGFR ligand sheddases. Here, we uncovered the sheddases for six EGFR ligands using mouse embryonic cells lacking candidate-releasing enzymes (a disintegrin and metalloprotease [ADAM] 9, 10, 12, 15, 17, and 19). ADAM10 emerged as the main sheddase of EGF and betacellulin, and ADAM17 as the major convertase of epiregulin, transforming growth factor {alpha}, amphiregulin, and heparin-binding EGF-like growth factor in these cells. Analysis of adam9/12/15/17-/- knockout mice corroborated the essential role of adam17-/- in activating the EGFR in vivo. This comprehensive evaluation of EGFR ligand shedding in a defined experimental system demonstrates that ADAMs have critical roles in releasing all EGFR ligands tested here. Identification of EGFR ligand sheddases is a crucial step toward understanding the mechanism underlying ectodomain release, and has implications for designing novel inhibitors of EGFR-dependent tumors.

Key Words: EGF receptor; EGF receptor ligands; ADAMs; ectodomain shedding; growth factor signaling

Abbreviations used in this paper: ADAM, a disintegrin and metalloprotease; AP, alkaline phosphatase; EGFR, epidermal growth factor receptor; GPCR, G protein–coupled receptor; HB-EGF, heparin-binding EGF-like growth factor; MEF, mouse embryonic fibroblast; TACE, TNF{alpha}-converting enzyme.


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