Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands Journal Article
| Authors: | Sahin, U.; Weskamp, G.; Kelly, K.; Zhou, H. M.; Higashiyama, S.; Peschon, J.; Hartmann, D.; Saftig, P.; Blobel, C. P. |
| Article Title: | Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands |
| 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 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. |
| Keywords: | epidermal growth factor; controlled study; intercellular signaling peptides and proteins; unclassified drug; nonhuman; protein domain; protein analysis; animal cell; mouse; animals; mice; mice, knockout; animal tissue; cells, cultured; protease inhibitors; embryo; epidermal growth factor receptor; cell protein; animal experiment; animal model; membrane proteins; genotype; in vivo study; receptor, epidermal growth factor; animalia; evaluation; ligand; protein secretion; fibroblasts; ligands; inhibition kinetics; protein structure, tertiary; glycoproteins; ligand binding; knockout mouse; amphiregulin; phenylalanine; heparin binding epidermal growth factor; transforming growth factor alpha; adam proteins; ectodomain shedding; amyloid precursor protein secretases; epiregulin; protein adam10; protein adam17; tetradecanoylphorbol acetate; endopeptidases; thiophenes; egf receptor; muscle proteins; protein adam12; protein adam15; protein adam19; protein adam9; aspartic endopeptidases; disintegrin; disintegrins; metalloendopeptidases; egf receptor ligands; priority journal; article; adams; growth factor signaling; betacellulin |
| Journal Title: | Journal of Cell Biology |
| Volume: | 164 |
| Issue: | 5 |
| ISSN: | 0021-9525 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2004-03-01 |
| Start Page: | 769 |
| End Page: | 779 |
| Language: | English |
| DOI: | 10.1083/jcb.200307137 |
| PROVIDER: | scopus |
| PMCID: | PMC2172154 |
| PUBMED: | 14993236 |
| DOI/URL: | |
| Notes: | J. Cell Biol. -- Cited By (since 1996):466 -- Export Date: 16 June 2014 -- CODEN: JCLBA -- Source: Scopus |
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