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Vol. 20, Issue 6, 1785-1794, March 15, 2009
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, L-Selectin, and Tumor Necrosis Factor 
,
*Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021; Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2937, Laboratoire d'Oncologie virale, 94801 Villejuif, France; Université Paris-Sud XI, 91405 Orsay, France; Biochemical Institute, Christian-Albrechts-University, 24098 Kiel, Germany; ||Department of Anti-aging Orthopedic Research and Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan; ¶Department of Inflammation, Schering Plough Research Institute, Kenilworth, NJ 07033-0539; #Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298; and @Departments of Medicine, and of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021
Submitted November 20, 2008;
Revised January 2, 2009;
Accepted January 9, 2009
Monitoring Editor: Benjamin Margolis
Protein ectodomain shedding is a critical regulator of many membrane proteins, including epidermal growth factor receptor-ligands and tumor necrosis factor (TNF)-
, providing a strong incentive to define the responsible sheddases. Previous studies identified ADAM17 as principal sheddase for transforming growth factor (TGF)- 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.
Address correspondence to: Carl P. Blobel (blobelc{at}hss.edu)
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