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• W1767906215 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." @default.
• W1767906215 created "2016-06-24" @default.
• W1767906215 creator A5010476642 @default.
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• W1767906215 date "2015-10-19" @default.
• W1767906215 modified "2023-10-16" @default.
• W1767906215 title "Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain" @default.
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• W1767906215 doi "https://doi.org/10.1038/srep15150" @default.
• W1767906215 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4609913" @default.
• W1767906215 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26477568" @default.
• W1767906215 hasPublicationYear "2015" @default.
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