Title | Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Miller, MA, Moss, ML, Powell, G, Petrovich, R, Edwards, L, Meyer, AS, Griffith, LG, Lauffenburger, DA |
Journal | Sci Rep |
Volume | 5 |
Pagination | 15150 |
Date Published | 2015 |
ISSN | 2045-2322 |
Abstract | Dysregulation of ErbB-family signaling underlies numerous pathologies and has been therapeutically targeted through inhibiting ErbB-receptors themselves or their cognate ligands. For the latter, "decoy" antibodies have been developed to sequester ligands including heparin-binding epidermal growth factor (HB-EGF); however, demonstrating sufficient efficacy has been difficult. Here, we hypothesized that this strategy depends on properties such as ligand-receptor binding affinity, which varies widely across the known ErbB-family ligands. Guided by computational modeling, we found that high-affinity ligands such as HB-EGF are more difficult to target with decoy antibodies compared to low-affinity ligands such as amphiregulin (AREG). To address this issue, we developed an alternative method for inhibiting HB-EGF activity by targeting its cleavage from the cell surface. In a model of the invasive disease endometriosis, we identified A Disintegrin and Metalloproteinase 12 (ADAM12) as a protease implicated in HB-EGF shedding. We designed a specific inhibitor of ADAM12 based on its recombinant prodomain (PA12), which selectively inhibits ADAM12 but not ADAM10 or ADAM17. In endometriotic cells, PA12 significantly reduced HB-EGF shedding and resultant cellular migration. Overall, specific inhibition of ligand shedding represents a possible alternative to decoy antibodies, especially for ligands such as HB-EGF that exhibit high binding affinity and localized signaling. |
DOI | 10.1038/srep15150 |
Alternate Journal | Sci Rep |
PubMed ID | 26477568 |
PubMed Central ID | PMC4609913 |
Grant List | R01 CA096504 / CA / NCI NIH HHS / United States R01-CA096504 / CA / NCI NIH HHS / United States U54 CA112967 / CA / NCI NIH HHS / United States U54-CA112967 / CA / NCI NIH HHS / United States |