ArticleCellular and molecular life sciences : CMLS2020
Homotrimeric MMP-9 is an active hitchhiker on alpha-2-macroglobulin partially escaping protease inhibition and internalization through LRP-1.
Article in Cellular and molecular life sciences : CMLS, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 35 citations in OpenAlex.
- An Oral Rinse Active Matrix Metalloproteinase-8 Point-of-Care Immunotest May Be Less Accurate in Patients with Crohn's Disease.Biomolecules · 2020Trial
- Systems Biology and Experimental Validation Enable Discovery of MMP9-Centered Networks, Anticancer Activity, and Pharmacodynamic Signature in Non-Small Cell Lung Cancer.International journal of molecular sciences · 2026Article
- Review
- Matrix Metalloproteinases in Inflammatory Dermatoses.International journal of molecular sciences · 2025Review
- Apolipoprotein-A1 transports and regulates MMP2 in the blood.Nature communications · 2025Article
- Zinc nanoparticles from oral supplements accumulate in renal tumours and stimulate antitumour immune responses.Nature materials · 2025Article
- Matrix metalloproteinases in arthritis: towards precision medicine.Nature reviews. Rheumatology · 2023Review
- Probing the binding of morin with alpha-2-macroglobulin using multi-spectroscopic and molecular docking approach : Interaction of morin with αJournal of biological physics · 2023Article
- Roles of constitutively secreted extracellular chaperones in neuronal cell repair and regeneration.Neural regeneration research · 2023Review
- Molecular Basis of Intestinal Fibrosis in Inflammatory Bowel Disease.Inflammatory intestinal diseases · 2023Review
- A2M Serves as Promising Biomarker for Chronic Obstructive Pulmonary Disease.International journal of chronic obstructive pulmonary disease · 2023Article
- How to place the duality of specific MMP-9 inhibition for treatment of inflammatory bowel diseases into clinical opportunities?Frontiers in immunology · 2022Review
- Extracellular Metalloproteinases in the Plasticity of Excitatory and Inhibitory Synapses.Cells · 2021Review
- Sialic acid removal by trans-sialidase modulates MMP-2 activity during Trypanosoma cruzi infection.Biochimie · 2021Article
- Structural characterisation of inhibitory and non-inhibitory MMP-9-TIMP-1 complexes and implications for regulatory mechanisms of MMP-9.Scientific reports · 2021Article
- Infarct in the Heart: What's MMP-9 Got to Do with It?Biomolecules · 2021Review
- Natural Marine and Terrestrial Compounds as Modulators of Matrix Metalloproteinases-2 (MMP-2) and MMP-9 in Alzheimer's Disease.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Alpha-2-Macroglobulin in Inflammation, Immunity and Infections.Frontiers in immunology · 2021Review
- Article
- Challenges in Matrix Metalloproteinases Inhibition.Biomolecules · 2020Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Proteolysis is a crucial process in life, tightly controlled by numerous natural protease inhibitors. In human blood, alpha-2-macroglobulin is an emergency protease inhibitor preventing coagulation and damage to endothelia and leukocytes. With the use of a unique protease trapping mechanism, alpha-2-macroglobulin lures active proteases into its snap-trap, shields these from potential substrates and 'flags' their complex for elimination by receptor-mediated endocytosis. Matrix metalloprotease-9/gelatinase B is a secreted protease increased in blood of patients with inflammations, vascular disorders and cancers. Matrix metalloprotease-9 occurs as monomers and stable homotrimers, but the reason for their co-existence remains obscure. We discovered that matrix metalloprotease-9 homotrimers undergo reduced anti-proteolytic regulation by alpha-2-macroglobulin and are able to travel as a proteolytically active hitchhiker on alpha-2-macroglobulin. As a comparison, we revealed that monomeric active matrix metalloprotease-9 is efficiently trapped by human plasma alpha-2-macroglobulin and this masks the detection of activated matrix metalloprotease-9 with standard analysis techniques. In addition, we show that alpha-2-macroglobulin/trimer complexes escape clearance through the receptor low-density lipoprotein receptor-related protein 1, also known as the alpha-2-macroglobulin receptor. Thus, the biochemistry and biology of matrix metalloprotease-9 monomers and trimers are completely different as multimerization enables active matrix metalloprotease-9 to partially avoid alpha-2-macroglobulin regulation both by direct protease inhibition and by removal from the extracellular space by receptor-mediated endocytosis. Finally, for the biomarker field, the analysis of alpha-2-macroglobulin/protease complexes with upgraded technology is advocated as a quotum for protease activation in human plasma samples.
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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.