Regulated ADAM17-dependent EGF family ligand release by substrate-selecting signaling pathways.

ABSTRACT: 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-? and the PKC-regulated protein phosphatase 1 inhibitor 14D that is required for ADAM17 cleavage of TGF-?, heparin-binding EGF, and amphiregulin. A second pathway involving PKC-? is required for neuregulin (NRG) cleavage, and, indeed, PKC-? 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.

SUBMITTER: Dang M 

PROVIDER: S-EPMC3683718 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature