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

作者：Le Gall Sylvain M; Bobe Pierre; Reiss Karina; Horiuchi Keisuke; Niu Xiao Da; Lundell Daniel; Gibb David R; Conrad Daniel; Saftig Paul; Blobel Carl P^*

来源：Molecular Biology of the Cell, 2009, 20(6): 1785-1794.

DOI：10.1091/mbc.E08-11-1135

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.

• 出版日期2009-3-15