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.

Sylvain M. Le Gall, Pierre Bobé, Karina Reiss, Keisuke Horiuchi, Xiao Da Niu, Daniel Lundell, David R. Gibb, Daniel Conrad, Paul Saftig, Carl P. Blobel

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1785-1794
Number of pages10
JournalMolecular Biology of the Cell
Volume20
Issue number6
Publication statusPublished - 2009 Mar
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Le Gall, S. M., Bobé, P., Reiss, K., Horiuchi, K., Niu, X. D., Lundell, D., Gibb, D. R., Conrad, D., Saftig, P., & Blobel, C. P. (2009). 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. Molecular Biology of the Cell, 20(6), 1785-1794.