Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain
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 fa...
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2015
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| Online Access: | http://hdl.handle.net/1721.1/100525 https://orcid.org/0000-0002-1801-5548 |
| _version_ | 1811081066871521280 |
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| author | Miller, Miles Aaron Moss, Marcia L. Powell, Gary Petrovich, Robert Edwards, Lori Griffith, Linda G. Lauffenburger, Douglas A. Meyer, Aaron Samuel |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Miller, Miles Aaron Moss, Marcia L. Powell, Gary Petrovich, Robert Edwards, Lori Griffith, Linda G. Lauffenburger, Douglas A. Meyer, Aaron Samuel |
| author_sort | Miller, Miles Aaron |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:41:08Z |
| format | Article |
| id | mit-1721.1/100525 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:41:08Z |
| publishDate | 2015 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1005252022-09-27T21:14:00Z Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain Miller, Miles Aaron Moss, Marcia L. Powell, Gary Petrovich, Robert Edwards, Lori Griffith, Linda G. Lauffenburger, Douglas A. Meyer, Aaron Samuel Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT Miller, Miles Aaron Meyer, Aaron Samuel Griffith, Linda G. Lauffenburger, Douglas A. 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. National Institutes of Health (U.S.) (Grant R01-CA096504) National Institutes of Health (U.S.) (Grant U54-CA112967) 2015-12-28T12:59:46Z 2015-12-28T12:59:46Z 2015-10 2015-01 Article http://purl.org/eprint/type/JournalArticle 2045-2322 http://hdl.handle.net/1721.1/100525 Miller, Miles A., Marcia L. Moss, Gary Powell, Robert Petrovich, Lori Edwards, Aaron S. Meyer, Linda G. Griffith, and Douglas A. Lauffenburger. “Targeting Autocrine HB-EGF Signaling with Specific ADAM12 Inhibition Using Recombinant ADAM12 Prodomain.” Scientific Reports 5 (October 19, 2015): 15150. https://orcid.org/0000-0002-1801-5548 en_US http://dx.doi.org/10.1038/srep15150 Scientific Reports Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Nature Publishing Group Nature Publishing Group |
| spellingShingle | Miller, Miles Aaron Moss, Marcia L. Powell, Gary Petrovich, Robert Edwards, Lori Griffith, Linda G. Lauffenburger, Douglas A. Meyer, Aaron Samuel Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain |
| title | Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain |
| title_full | Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain |
| title_fullStr | Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain |
| title_full_unstemmed | Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain |
| title_short | Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain |
| title_sort | targeting autocrine hb egf signaling with specific adam12 inhibition using recombinant adam12 prodomain |
| url | http://hdl.handle.net/1721.1/100525 https://orcid.org/0000-0002-1801-5548 |
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