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
| Autor: | Daniel Lundell, Carl P. Blobel, Xiao Da Niu, Karina Reiss, Sylvain Le Gall, David R. Gibb, Keisuke Horiuchi, Pierre Bobe, Daniel Conrad, Paul Saftig |
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| Rok vydání: | 2009 |
| Předmět: |
TGF alpha
ADAM10 Biology ADAM17 Protein Substrate Specificity ADAM10 Protein Mice Epidermal growth factor Animals Humans Growth factor receptor inhibitor Protease Inhibitors Epidermal growth factor receptor L-Selectin Molecular Biology Cells Cultured Mice Knockout Tumor Necrosis Factor-alpha Membrane Proteins Cell Biology Articles Sheddase Transforming Growth Factor alpha Molecular biology Cell biology ADAM Proteins biology.protein Calcium RNA Interference Amyloid Precursor Protein Secretases Transforming growth factor Signal Transduction |
| Zdroj: | Molecular biology of the cell. 20(6) |
| ISSN: | 1939-4586 |
| Popis: | Protein ectodomain shedding is a critical regulator of many membrane proteins, including epidermal growth factor receptor-ligands and tumor necrosis factor (TNF)-α, providing a strong incentive to define the responsible sheddases. Previous studies identified ADAM17 as principal sheddase for transforming growth factor (TGF)-α 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. |
| Databáze: | OpenAIRE |
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