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Molecular and Cellular Biology, July 2006, p. 5086-5095, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.02380-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Proteomic Identification of Desmoglein 2 and Activated Leukocyte Cell Adhesion Molecule as Substrates of ADAM17 and ADAM10 by Difference Gel Electrophoresis{dagger}

Joan J. Bech-Serra,2 Belén Santiago-Josefat,2 Cary Esselens,2 Paul Saftig,3 José Baselga,2 Joaquín Arribas,2* and Francesc Canals1,2

Proteomics Laboratory,1 Medical Oncology Research Program, Vall d'Hebron University Hospital Research Institute, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain,2 Institute of Biochemistry, University of Kiel, D-24118 Kiel, Germany3

Received 14 December 2005/ Returned for modification 18 January 2006/ Accepted 7 April 2006

In contrast with the early view of metalloproteases as simple extracellular matrix-degrading entities, recent findings show that they are highly specific modulators of different signaling pathways involved, positively or negatively, in tumor development. Thus, before considering a given metalloprotease a therapeutic target, it seems advisable to characterize its function by identifying its repertoire of substrates. Here, we present a proteomic approach to identify ADAM17 substrates by difference gel electrophoresis. We found that the shedding of the extracellular domain of the transferrin receptor and those of two cell-cell adhesion molecules, activated leukocyte cell adhesion molecule (ALCAM) and desmoglein 2 (Dsg-2), is increased in cells overexpressing ADAM17. Genetic evidence shows that while ADAM17 is responsible for the shedding of ALCAM, both ADAM17 and ADAM10 can act on Dsg-2. Activation of the epidermal growth factor receptor leads to the upregulation of the shedding of Dsg-2 and to the concomitant upregulation of ADAM17, but not ADAM10, supporting the ability of overexpressed ADAM17 to shed Dsg-2. These results unveil a role of ADAM10 and ADAM17 in the shedding of cell-cell adhesion molecules. Since loss of cell adhesion is an early event in tumor development, these results suggest that ADAM17 is a useful target in anticancer therapy.

* Corresponding author. Mailing address: Medical Oncology Research Program, Vall d'Hebron University Hospital Research Institute, 08035 Barcelona, Spain. Phone: 34 93 274 6026. Fax: 34 93 274 6026. E-mail: jarribas{at}ir.vhebron.net.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, July 2006, p. 5086-5095, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.02380-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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