title: ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor alpha, L-selectin, and tumor necrosis factor alpha.
abstract: Protein ectodomain shedding is a critical regulator of many membrane proteins, including epidermal growth factor receptor-ligands and tumor necrosis factor (TNF)-alpha, providing a strong incentive to define the responsible sheddases. Previous studies identified ADAM17 as principal sheddase for transforming growth factor (TGF)-alpha and heparin-binding epidermal growth factor, but Ca++ influx activated an additional sheddase for these epidermal growth factor receptor ligands in Adam17-/- cells. Here, we show that Ca++ influx and stimulation of the P2X7R signaling pathway activate ADAM10 as sheddase of many ADAM17 substrates in Adam17-/- fibroblasts and primary B cells. Importantly, although ADAM10 can shed all substrates of ADAM17 tested here in Adam17-/- cells, acute treatment of wild-type cells with a highly selective ADAM17 inhibitor (SP26) showed that ADAM17 is nevertheless the principal sheddase when both ADAMs 10 and 17 are present. However, chronic treatment of wild-type cells with SP26 promoted processing of ADAM17 substrates by ADAM10, thus generating conditions such as in Adam17-/- cells. These results have general implications for understanding the substrate selectivity of two major cellular sheddases, ADAMs 10 and 17.
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Sylvain M
authors.initials: SM
authors.lastname: Le Gall
authors.forename: Pierre
authors.initials: P
authors.lastname: Bobé
authors.forename: Karina
authors.initials: K
authors.lastname: Reiss
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horiuchi
authors.forename: Xiao-Da
authors.initials: XD
authors.lastname: Niu
authors.forename: Daniel
authors.initials: D
authors.lastname: Lundell
authors.forename: David R
authors.initials: DR
authors.lastname: Gibb
authors.forename: Daniel
authors.initials: D
authors.lastname: Conrad
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D019041:L-Selectin / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D011480:Protease Inhibitors; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D002118:Calcium