title: 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-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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Dang
authors.forename: Nicole
authors.initials: N
authors.lastname: Armbruster
authors.forename: Miles A
authors.initials: MA
authors.lastname: Miller
authors.forename: Efrain
authors.initials: E
authors.lastname: Cermeno
authors.forename: Monika
authors.initials: M
authors.lastname: Hartmann
authors.forename: George W
authors.initials: GW
authors.lastname: Bell
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.forename: Harvey F
authors.initials: HF
authors.lastname: Lodish
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrlich
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D066258:Amphiregulin; D000804:Angiotensin II / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D066255:EGF Family of Proteins; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005434:Flow Cytometry; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D019169:Jurkat Cells; D008024:Ligands; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D034622:RNA Interference; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008024:Ligands; C480492:PPP1R14D protein, human; D011506:Proteins; D016211:Transforming Growth Factor alpha; D000804:Angiotensin II; D012694:Serine; D004815:Epidermal Growth Factor; D011493:Protein Kinase C; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D013755:Tetradecanoylphorbol Acetate
keywords: epidermal growth factor receptor; transactivation