1. Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands.
- Author
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Sahin U, Weskamp G, Kelly K, Zhou HM, Higashiyama S, Peschon J, Hartmann D, Saftig P, and Blobel CP
- Subjects
- ADAM Proteins, ADAM12 Protein, ADAM17 Protein, Amphiregulin, Amyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Betacellulin, Cells, Cultured, Disintegrins genetics, Disintegrins metabolism, EGF Family of Proteins, Embryo, Mammalian anatomy & histology, Endopeptidases genetics, Epidermal Growth Factor metabolism, Epiregulin, Fibroblasts cytology, Fibroblasts metabolism, Genotype, Glycoproteins metabolism, Heparin-binding EGF-like Growth Factor, Intercellular Signaling Peptides and Proteins metabolism, Ligands, Membrane Proteins genetics, Membrane Proteins metabolism, Metalloendopeptidases genetics, Mice, Mice, Knockout, Muscle Proteins genetics, Muscle Proteins metabolism, Phenylalanine metabolism, Protease Inhibitors metabolism, Protein Structure, Tertiary, Tetradecanoylphorbol Acetate metabolism, Thiophenes metabolism, Transforming Growth Factor alpha metabolism, Endopeptidases metabolism, ErbB Receptors metabolism, Metalloendopeptidases metabolism, Phenylalanine analogs & derivatives
- Abstract
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.
- Published
- 2004
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