ArticleOncogenesis2013
A monoclonal antibody interferes with TIMP-2 binding and incapacitates the MMP-2-activating function of multifunctional, pro-tumorigenic MMP-14/MT1-MMP.
Article in Oncogenesis, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
What it found
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The trial behind it
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
26 citing papers in PubMed, 43 citations in OpenAlex.
- Achieving protease substrate-specific inhibition by mAb dual functional selections.Protein science : a publication of the Protein Society · 2026Article
- Review
- Identification of small molecule inhibitors against MMP-14 via High-Throughput screening.Bioorganic & medicinal chemistry · 2023Article
- Identification of amino acid residues in the MT-loop of MT1-MMP critical for its ability to cleave low-density lipoprotein receptor.Frontiers in cardiovascular medicine · 2022Article
- Membrane-type I matrix metalloproteinase (MT1-MMP), lipid metabolism, and therapeutic implications.Journal of molecular cell biology · 2021Review
- Generation of highly selective monoclonal antibodies inhibiting a recalcitrant protease using decoy designs.Biotechnology and bioengineering · 2020Article
- Inhibiting Matrix Metalloproteinase-2 Activation by Perturbing Protein-Protein Interactions Using a Cyclic Peptide.Journal of medicinal chemistry · 2020Article
- Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics.Cells · 2020Review
- Immunoproteomic Identification of Noncarbohydrate Antigens Eliciting Graft-Specific Adaptive Immune Responses in Patients with Bovine Pericardial Bioprosthetic Heart Valves.Proteomics. Clinical applications · 2019Article
- Inhibitory Antibodies Designed for Matrix Metalloproteinase Modulation.Molecules (Basel, Switzerland) · 2019Review
- Monoclonal antibodies against metzincin targets.British journal of pharmacology · 2019Review
- Mechanisms of Action of Novel Drugs Targeting Angiogenesis-Promoting Matrix Metalloproteinases.Frontiers in immunology · 2019Review
- Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer.Journal of cellular biochemistry · 2017Review
- Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain.Brain, behavior, and immunity · 2017Article
- Selective function-blocking monoclonal human antibody highlights the important role of membrane type-1 matrix metalloproteinase (MT1-MMP) in metastasis.Oncotarget · 2017Article
- Active-site MMP-selective antibody inhibitors discovered from convex paratope synthetic libraries.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Role of Matrix Metalloproteinases in the Pathogenesis of Traumatic Brain Injury.Molecular neurobiology · 2016Review
- Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism.Journal of the American Heart Association · 2016Article
- Limited independent prognostic value of MMP-14 and MMP-2 expression in ovarian cancer.Diagnostic pathology · 2016Article
- Development of a specific affinity-matured exosite inhibitor to MT1-MMP that efficiently inhibits tumor cell invasion in vitro and metastasis in vivo.Oncotarget · 2016Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Matrix metalloproteinases (MMPs) and, especially membrane type 1 (MT1)-MMP/MMP-14, are promising drug targets in malignancies. In contrast with multiple small-molecule and protein pan-inhibitors of MT1-MMP cleavage activity, the murine 9E8 monoclonal antibody targets the MMP-2-activating function of cellular MT1-MMP alone, rather than the general proteolytic activity and the pro-migratory function of MT1-MMP. Furthermore, the antibody does not interact in any detectable manner with other members of the membrane type (MT)-MMP family. The mechanism of this selectivity remained unknown. Using mutagenesis, binding and activity assays, and modeling in silico, we have demonstrated that the 9E8 antibody recognizes the MT-loop structure, an eight residue insertion that is specific for MT-MMPs and that is distant from the MT1-MMP active site. The binding of the 9E8 antibody to the MT-loop, however, prevents tissue inhibitor of metalloproteinases-2 (TIMP-2) association with MT1-MMP. As a result, the 9E8 antibody incapacitates the TIMP-2-dependent MMP-2-activating function alone rather than the general enzymatic activity of human MT1-MMP. The specific function of the 9E8 antibody we determined directly supports an essential, albeit paradoxical, role of the protein inhibitor (TIMP-2) in MMP-2 activation via a unique membrane-tethered mechanism. In this mechanism, the formation of a tri-molecular MT1-MMPTIMP-2MMP-2 complex is required for both the capture of the soluble MMP-2 proenzyme by cells and then its well-controlled conversion into the mature MMP-2 enzyme. In sum, understanding of the structural requirements for the 9E8 antibody specificity may pave the way for the focused design of the inhibitory antibodies against other individual MMPs.
Identifiers
What OpenQuestion holds
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.