ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor α, l-selectin, and tumor necrosis factor α

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

171 Citations (Scopus)

Abstract

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 AdamT7-l- cells. Here, we show that Ca ++ influx and stimulation of the P2X7R signaling pathway activate ADAM10 as sheddase of many ADAM17 substrates in Adam17-l- fibroblasts and primary B cells. Importantly, although ADAM10 can shed all substrates of ADAM17 tested here in Adam17-l- 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-l- 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)1772-1784
Number of pages13
JournalMolecular biology of the cell
Volume20
Issue number6
DOIs
Publication statusPublished - 2009 Mar 15

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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