Journal
JOURNAL OF CELL BIOLOGY
Volume 164, Issue 5, Pages 769-779Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200307137
Keywords
EGF receptor; EGF receptor ligands; ADAMs; ectodomain shedding; growth factor signaling
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Funding
- NCI NIH HHS [P30 CA008748, P30-CA-08748] Funding Source: Medline
- NIGMS NIH HHS [F32 GM065740, R01 GM064750, R01 GM65740, R01 GM064750-06] Funding Source: Medline
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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 [ADAM] 7 as the major convertase of epiregulin, transforming growth factor a, 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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