Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands

TLDR

EGFR ligands are released from the cell membrane by proteases, and ectodomain shedding is essential for their activation, making the identification of the responsible sheddases a key research priority. Using mouse embryonic cells deficient in candidate ADAM proteases (ADAM9, 10, 12, 15, 17, and 19), the study mapped the sheddases for six EGFR ligands. ADAM10 is the primary sheddase for EGF and betacellulin, while ADAM17 mediates shedding of epiregulin, TGF‑α, amphiregulin, and HB‑EGF, and knockout mice confirm ADAM17’s essential role, underscoring that ADAMs are critical for releasing all tested EGFR ligands and informing inhibitor design.

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.