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

By U. Şahin, G. Weskamp, Kristine Kelly, Hong-Ming Zhou, S. Higashiyama, J. Peschon, D. Hartmann, P. Saftig, C. Blobel. 2004

1,035 citations recorded by the source corpus.

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.

Subfields: Oncology, Radiology, Nuclear Medicine and Imaging

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In Oncology

1. S. Zhong
2. R. Khalil
3. D. Edwards
4. M. Handsley
5. C. Pennington
6. J. Guan
7. C. Blobel
8. C. Iadecola

In Radiology, Nuclear Medicine and Imaging

1. C. Blobel

Citations in the corpus

• A Disintegrin and Metalloproteinase (ADAM) and ADAM with Thrombospondin Motifs (ADAMTS) Family in Vascular Biology and Disease (2019, background): “Activation of EGFR, through the shedding of membrane-anchored pro-TGFα [85] and pro-HB-EGF [98], is among the critical functions of ADAM-17 [99– 101], when compared to other candidate HB-EGF sheddases such as ADAM-9, 12 and 15 [18, 102].”
• Metalloprotease‐disintegrin ADAM8: Expression analysis and targeted deletion in mice (2005, background): “Only approximately half of the known ADAMs contain the catalytic site consensus sequence for metalloproteases (HEXXHXXGXXHD; Stocker et al., 1995; Sahin et al., 2004), and ADAMs lacking this site most likely do not possess metalloprotease activity.”
• ADAM10 is the physiologically relevant, constitutive α‐secretase of the amyloid precursor protein in primary neurons (2010, background): “: þ 49 89 218075453; Fax: þ 49 89 218075415; E-mail: stefan.lichtenthaler@med.uni-muenchen.de 5These authors contributed equally to this work The EMBO Journal (2010) 29, 3020–3032 | & 2010 European Molecular Biology Organization | All Rights Reserved 0261-4189/10 www.embojournal.org The EMBO Journal”
• Role of aberrant metalloproteinase activity in the pro-inflammatory phenotype of bronchial epithelium in COPD (2011, background): “The PMA-induced TGF-a shedding was completely blocked by ADAM17/10 inhibitor GW280264 (Figure 1C), but was not affected by specific ADAM10 inhibitor GI254023 (additional file 2, Figure S2), indicating that ADAM17 is the main PMA-induced sheddase of TGF-a upon PBEC activation.”
• Deletion of Cdc42 Enhances ADAM17-Mediated Vascular Endothelial Growth Factor Receptor 2 Shedding and Impairs Vascular Endothelial Cell Survival and Vasculogenesis (2013, methodology): “To identify which ADAM family member(s) is involved in the production of the 75-kDa VEGFR2 fragment, we stimulated HUVECs with phorbol-12-myristate-13-acetate (PMA) or ionomycin (IM), which have been reported to activate ADAM17 or ADAM10, respectively (45, 46, 48).”
• ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. (2006, neutral): “In ADAM17 / mouse embryonic fibroblasts, shedding of TGF- , amphiregulin, epiregulin, or HBEGF induced by the phorbol ester, phorbol 12-myristrate 13-acetate (PMA) was significantly decreased compared with wild-type cells (82), suggesting a critical role of PKC in ADAM17 activation.”