Regulated ADAM17-dependent EGF family ligand release by substrate-selecting signaling pathways
Author(s)Dang, Michelle; Armbruster, Nicole; Miller, Miles Aaron; Cermeno, Efrain A.; Hartmann, Monika; Bell, George W.; Root, David E.; Lauffenburger, Douglas A.; Lodish, Harvey F.; Herrlich, Andreas; ... Show more Show less
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Ectodomain cleavage of cell-surface proteins by A disintegrin and metalloproteinases (ADAMs) is highly regulated, and its dysregulation has been linked to many diseases. ADAM10 and ADAM17 cleave most disease-relevant substrates. Broad-spectrum metalloprotease inhibitors have failed clinically, and targeting the cleavage of a specific substrate has remained impossible. It is therefore necessary to identify signaling intermediates that determine substrate specificity of cleavage. We show here that phorbol ester or angiotensin II-induced proteolytic release of EGF family members may not require a significant increase in ADAM17 protease activity. Rather, inducers activate a signaling pathway using PKC-α and the PKC-regulated protein phosphatase 1 inhibitor 14D that is required for ADAM17 cleavage of TGF-α, heparin-binding EGF, and amphiregulin. A second pathway involving PKC-δ is required for neuregulin (NRG) cleavage, and, indeed, PKC-δ phosphorylation of serine 286 in the NRG cytosolic domain is essential for induced NRG cleavage. Thus, signaling-mediated substrate selection is clearly distinct from regulation of enzyme activity, an important mechanism that offers itself for application in disease.
DepartmentMassachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology
Proceedings of the National Academy of Sciences
National Academy of Sciences (U.S.)
Dang, M., N. Armbruster, M. A. Miller, E. Cermeno, M. Hartmann, G. W. Bell, D. E. Root, D. A. Lauffenburger, H. F. Lodish, and A. Herrlich. “Regulated ADAM17-dependent EGF family ligand release by substrate-selecting signaling pathways.” Proceedings of the National Academy of Sciences 110, no. 24 (June 11, 2013): 9776-9781. © 2013 National Academy of Sciences.
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