ArticleScientific reports2015
Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain.
Article in Scientific reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 26 citations in OpenAlex.
- Identification of potent inhibitors of JUN N-terminal kinases for treatment of endometriosis and associated pain.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- ADAM17-mediated EGFR ligand shedding directs macrophage-promoted cancer cell invasion.JCI insight · 2022Article
- Lysophospholipid Mediators in Health and Disease.Annual review of pathology · 2022Review
- Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis.International journal of molecular sciences · 2020Review
- ADAM-Mediated Signalling Pathways in Gastrointestinal Cancer Formation.International journal of molecular sciences · 2020Review
- In vivo microscopy reveals macrophage polarization locally promotes coherent microtubule dynamics in migrating cancer cells.Nature communications · 2020Article
- Single-Cell Intravital Microscopy of Trastuzumab Quantifies Heterogeneous in vivo Kinetics.Cytometry. Part A : the journal of the International Society for Analytical Cytology · 2020Article
- Review
- Article
- Identification of ADAM12 as a Novel Basigin Sheddase.International journal of molecular sciences · 2019Article
- Modular Nanoparticulate Prodrug Design Enables Efficient Treatment of Solid Tumors Using Bioorthogonal Activation.ACS nano · 2018Article
- The Transcriptome of Estrogen-Independent Mammary Growth in Female Mice Reveals That Not All Mammary Glands Are Created Equally.Endocrinology · 2017Article
- Autotaxin-lysophosphatidic acid-LPAThe EMBO journal · 2017Article
- Imaging the pharmacology of nanomaterials by intravital microscopy: Toward understanding their biological behavior.Advanced drug delivery reviews · 2017Review
- Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Review
- Fine Tuning Cell Migration by a Disintegrin and Metalloproteinases.Mediators of inflammation · 2017Review
- MenaINV mediates synergistic cross-talk between signaling pathways driving chemotaxis and haptotaxis.Molecular biology of the cell · 2016Article
- ADAM and ADAMTS Family Proteins and Snake Venom Metalloproteinases: A Structural Overview.Toxins · 2016Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.