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 α, 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.
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1 March 2004
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March 01 2004
Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands
Umut Sahin,
Umut Sahin
1Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
2Department of Molecular and Cellular Biology and Biochemistry, Brown University, Providence, RI 02912
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Gisela Weskamp,
Gisela Weskamp
1Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
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Kristine Kelly,
Kristine Kelly
1Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
3Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021
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Hong-Ming Zhou,
Hong-Ming Zhou
1Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
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Shigeki Higashiyama,
Shigeki Higashiyama
4Department of Medical Biochemistry, Ehime University School of Medicine, Ehime 791-0301, Japan
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Jacques Peschon,
Jacques Peschon
5Amgen Inc., Seattle, WA 98101
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Dieter Hartmann,
Dieter Hartmann
6Department for Human Genetics, K.U. Leuven and Flanders Interuniversity Institute for Biotechnology (VIB-4), 3000 Leuven, Belgium
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Paul Saftig,
Paul Saftig
7Biochemical Institute, Christian-Albrechts University, D-24098 Kiel, Germany
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Carl P. Blobel
Carl P. Blobel
1Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
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Umut Sahin
1Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
2Department of Molecular and Cellular Biology and Biochemistry, Brown University, Providence, RI 02912
Gisela Weskamp
1Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
Kristine Kelly
1Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
3Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021
Hong-Ming Zhou
1Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
Shigeki Higashiyama
4Department of Medical Biochemistry, Ehime University School of Medicine, Ehime 791-0301, Japan
Jacques Peschon
5Amgen Inc., Seattle, WA 98101
Dieter Hartmann
6Department for Human Genetics, K.U. Leuven and Flanders Interuniversity Institute for Biotechnology (VIB-4), 3000 Leuven, Belgium
Paul Saftig
7Biochemical Institute, Christian-Albrechts University, D-24098 Kiel, Germany
Carl P. Blobel
1Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
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: [email protected]
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, TNFα-converting enzyme.
Received:
July 21 2003
Accepted:
January 13 2004
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2004
J Cell Biol (2004) 164 (5): 769–779.
Article history
Received:
July 21 2003
Accepted:
January 13 2004
Citation
Umut Sahin, Gisela Weskamp, Kristine Kelly, Hong-Ming Zhou, Shigeki Higashiyama, Jacques Peschon, Dieter Hartmann, Paul Saftig, Carl P. Blobel; Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands . J Cell Biol 1 March 2004; 164 (5): 769–779. doi: https://doi.org/10.1083/jcb.200307137
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