Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis
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We have uncovered a novel functional relationship between the hyaluronan receptor CD44, the matrix metalloproteinase-9 (MMP-9) and the multifunctional cytokine TGF-β in the control of tumor-associated tissue remodeling. CD44 provides a cell surface docking receptor for proteolytically active MMP-9 and we show here that localization of MMP-9 to cell surface is required for its ability to promote tumor invasion and angiogenesis. Our observations also indicate that MMP-9, as well as MMP-2, proteolytically cleaves latent TGF-β, providing a novel and potentially important mechanism for TGF-β activation. In addition, we show that MMP-9 localization to the surface of normal keratinocytes is CD44 dependent and can activate latent TGF-β. These observations suggest that coordinated CD44, MMP-9, and TGF-β function may provide a physiological mechanism of tissue remodeling that can be adopted by malignant cells to promote tumor growth and invasion.
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Liver macrophages from CCl4-injured Ccn1 D125A/D125A mice expressed lower levels of Mmp9- and Mmp13-encoding proteases implicated in activation of TGF-β1.
“and lower levels of matrix metallopeptidase 9 (Mmp9)‐ and Mmp13‐encoding proteases implicated in the activation of TGF‐β1 (Figure S4B).[ 29 , 30 ]”
From Cellular communication network factor 1‐stimulated liver macrophage efferocytosis drives hepatic stellate cell activation and liver fibrosis (2022) · cites this paper as [29]
IL-6-induced MMP9 converts matrix-bound latent TGF-β into its active form.
“For example, IL-6–mediated induction of MMP9 (ref. 84) converts the matrix-tethered latent TGF-β complex to an active form 85.”
From The central role of muscle stem cells in regenerative failure with aging (2015) · cites this paper as [85]
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Mesenchymal stem cells promote tumor angiogenesis via the action of transforming growth factor β1
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Transcriptome Analysis of CHO Cell Size Increase During a Fed-Batch Process
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- Authors
- Yu, Q., & Stamenkovic, I.
- Affiliations
- Harvard University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2000-01-15
- Volume
- 14
- Issue
- 2
- Pages
- 163-176
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W4294352168
- Cited by
- 1,754
- References
- 40
- Citations by year
- 2026: 31 · 2025: 49 · 2024: 43 · 2023: 55 · 2022: 57 · 2021: 78 · 2020: 57 · 2019: 67 · 2018: 68 · 2017: 83 · 2016: 68 · 2015: 93 · 2014: 90 · 2013: 85 · 2012: 68
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Funders
- National Institutes of Health (GM48614)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Keywords
- MMP-9, TGF-beta activation, CD44, hyaluronan receptor, tumor invasion, angiogenesis, MMP-2, cell surface localization, tissue remodeling, keratinocytes, tumor growth
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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