ArticleThe Journal of biological chemistry2014
Noncanonical activation of Notch1 protein by membrane type 1 matrix metalloproteinase (MT1-MMP) controls melanoma cell proliferation.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 37 citations in OpenAlex.
- Targeting the microbiota-miRNA-protease axis: A new therapeutic avenue in melanoma.The FEBS journal · 2026Review
- A guide to the types, structures, and multifaceted functions of matrix metalloproteinases in cancer.The FEBS journal · 2026Review
- The dual role of the Notch signaling pathway in digestive system cancers.European journal of medical research · 2026Review
- Significance of Notch Signaling in Salivary Gland Development and Diseases.Journal of clinical medicine · 2025Review
- Potential target within the tumor microenvironment - MT1-MMP.Frontiers in immunology · 2025Review
- Notch signaling pathway in cancer: from mechanistic insights to targeted therapies.Signal transduction and targeted therapy · 2024Review
- Stromal Cells Present in the Melanoma Niche Affect Tumor Invasiveness and Its Resistance to Therapy.International journal of molecular sciences · 2021Review
- MT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart.PloS one · 2021Article
- Targeting Extracellular Matrix Remodeling Restores BRAF Inhibitor Sensitivity in BRAFi-resistant Melanoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2020Article
- Coronin 1C inhibits melanoma metastasis through regulation of MT1-MMP-containing extracellular vesicle secretion.Scientific reports · 2020Article
- Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis.Cancer letters · 2020Article
- Upregulated expression of MMP family genes is associated with poor survival in patients with esophageal squamous cell carcinoma via regulation of proliferation and epithelial‑mesenchymal transition.Oncology reports · 2020Article
- APE1 Upregulates MMP-14 via Redox-Sensitive ARF6-Mediated Recycling to Promote Cell Invasion of Esophageal Adenocarcinoma.Cancer research · 2019Article
- The Expanding Role of MT1-MMP in Cancer Progression.Pharmaceuticals (Basel, Switzerland) · 2019Review
- The membrane tethered matrix metalloproteinase MT1-MMP triggers an outside-in DNA damage response that impacts chemo- and radiotherapy responses of breast cancer.Cancer letters · 2019Article
- Exploring major signaling cascades in melanomagenesis: a rationale route for targetted skin cancer therapy.Bioscience reports · 2018Review
- The thiirane-based selective MT1-MMP/MMP2 inhibitor ND-322 reduces melanoma tumor growth and delays metastatic dissemination.Pharmacological research · 2016Article
- Targeting Notch to overcome radiation resistance.Oncotarget · 2016Review
- Ligand-Independent Mechanisms of Notch Activity.Trends in cell biology · 2015Review
- Notch1 Autoactivation via Transcriptional Regulation of Furin, Which Sustains Notch1 Signaling by Processing Notch1-Activating Proteases ADAM10 and Membrane Type 1 Matrix Metalloproteinase.Molecular and cellular biology · 2015Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Notch1 is an evolutionarily conserved signaling molecule required for stem cell maintenance that is inappropriately reactivated in several cancers. We have previously shown that melanomas reactivate Notch1 and require its function for growth and survival. However, no Notch1-activating mutations have been observed in melanoma, suggesting the involvement of other activating mechanisms. Notch1 activation requires two cleavage steps: first by a protease and then by γ-secretase, which releases the active intracellular domain (Notch1(NIC)). Interestingly, although ADAM10 and -17 are generally accepted as the proteases responsible of Notch1 cleavage, here we show that MT1-MMP, a membrane-tethered matrix metalloproteinase involved in the pathogenesis of a number of tumors, is a novel protease required for the cleavage of Notch1 in melanoma cells. We find that active Notch1 and MT1-MMP expression correlate significantly in over 70% of melanoma tumors and 80% of melanoma cell lines, whereas such correlation does not exist between Notch1(NIC) and ADAM10 or -17. Modulation of MT1-MMP expression in melanoma cells affects Notch1 cleavage, whereas MT1-MMP expression in ADAM10/17 double knock-out fibroblasts restores the processing of Notch1, indicating that MT1-MMP is sufficient to promote Notch1 activation independently of the canonical proteases. Importantly, we find that MT1-MMP interacts with Notch1 at the cell membrane, supporting a potential direct cleavage mechanism of MT1-MMP on Notch1, and that MT1-MMP-dependent activation of Notch1 sustains melanoma cell growth. Together, the data highlight a novel mechanism of activation of Notch1 in melanoma cells and identify Notch1 as a new MT1-MMP substrate that plays important biological roles in melanoma.
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