title: Ectodomain shedding of the EGF-receptor ligand epigen is mediated by ADAM17.
abstract: All ligands of the epidermal growth factor receptor (EGFR), which has important roles in development and disease, are made as transmembrane precursors. Proteolytic processing by ADAMs (a disintegrin and metalloprotease) regulates the bioavailability of several EGFR-ligands, yet little is known about the enzyme responsible for processing the recently identified EGFR ligand, epigen. Here we show that ectodomain shedding of epigen requires ADAM17, which can be stimulated by phorbol esters, phosphatase inhibitors and calcium influx. These results suggest that ADAM17 might be a good target to block the release of bioactive epigen, a highly mitogenic ligand of the EGFR which has been implicated in wound healing and cancer.
authors.affiliation: Arthritis and Tissue Degeneration Program, Caspary Research Building, Room 426, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Umut
authors.initials: U
authors.lastname: Sahin
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066261:Epigen; D066246:ErbB Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics
chemical_list: C587854:EPGN protein, human; C587855:Epgn protein, mouse; D066261:Epigen; D006133:Growth Substances; D008024:Ligands; D008565:Membrane Proteins; D011480:Protease Inhibitors; D011498:Protein Precursors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse