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Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands.
- Source :
-
The Journal of cell biology [J Cell Biol] 2004 Mar 01; Vol. 164 (5), pp. 769-79. - Publication Year :
- 2004
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9525
- Volume :
- 164
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 14993236
- Full Text :
- https://doi.org/10.1083/jcb.200307137