ArticleScientific reports2017
Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 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
49 citing papers in PubMed, 85 citations in OpenAlex.
- Lymphatic Endothelial Cells in Health and Disease.MedComm · 2026Review
- [Research progress on vascular endothelial growth factor C in meningeal lymphatic vessel-mediated clearance of amyloid β-protein].Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2026Review
- The role of the cardiac lymphatic system in heart failure "reverse remodeling": from developmental signals to druggable targets.Frontiers in immunology · 2026Review
- Further characterisation of immortalised human lymphatic endothelial cells to explore their transcriptomic profile and VEGFC response.Scientific reports · 2025Article
- Vascular endothelial generating factor pathway in ovarian cancer.Journal of ovarian research · 2025Review
- Meningeal lymphatic drainage: novel insights into central nervous system disease.Signal transduction and targeted therapy · 2025Review
- Regulation of VEGFR3 signaling in lymphatic endothelial cells.Frontiers in cell and developmental biology · 2025Review
- Central conducting lymphatic anomaly: from bench to bedside.The Journal of clinical investigation · 2024Review
- Visfatin Affects the Transcriptome of Porcine Luteal Cells during Early Pregnancy.International journal of molecular sciences · 2024Article
- Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema.EMBO molecular medicine · 2024Article
- Article
- Structural and functional analysis of the newt lymphatic system.Scientific reports · 2023Article
- Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation.The Journal of experimental medicine · 2023Article
- Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments.Molecular cancer · 2023Review
- Downregulation of ADAMTS3 Suppresses Stemness and Tumorigenicity in Glioma Stem Cell.CNS neuroscience & therapeutics · 2023Article
- Bioactive VEGF-C from E. coli.Scientific reports · 2022Article
- Osteopathy in Complex Lymphatic Anomalies.International journal of molecular sciences · 2022Review
- The Mechanism and Role of ADAMTS Protein Family in Osteoarthritis.Biomolecules · 2022Review
- Molecular Mechanisms of Tumor Immunomodulation in the Microenvironment of Colorectal Cancer.International journal of molecular sciences · 2022Review
- Chinese Herbal Medicine Adjusting Brain Microenvironment via Mediating Central Nervous System Lymphatic Drainage in Alzheimer's Disease.Chinese journal of integrative medicine · 2022Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
The collagen- and calcium-binding EGF domains 1 (CCBE1) protein is necessary for lymphangiogenesis. Its C-terminal collagen-like domain was shown to be required for the activation of the major lymphangiogenic growth factor VEGF-C (Vascular Endothelial Growth Factor-C) along with the ADAMTS3 (A Disintegrin And Metalloproteinase with Thrombospondin Motifs-3) protease. However, it remained unclear how the N-terminal domain of CCBE1 contributed to lymphangiogenic signaling. Here, we show that efficient activation of VEGF-C requires its C-terminal domain both in vitro and in a transgenic mouse model. The N-terminal EGF-like domain of CCBE1 increased VEGFR-3 signaling by colocalizing pro-VEGF-C with its activating protease to the lymphatic endothelial cell surface. When the ADAMTS3 amounts were limited, proteolytic activation of pro-VEGF-C was supported by the N-terminal domain of CCBE1, but not by its C-terminal domain. A single amino acid substitution in ADAMTS3, identified from a lymphedema patient, was associated with abnormal CCBE1 localization. These results show that CCBE1 promotes VEGFR-3 signaling and lymphangiogenesis by different mechanisms, which are mediated independently by the two domains of CCBE1: by enhancing the cleavage activity of ADAMTS3 and by facilitating the colocalization of VEGF-C and ADAMTS3. These new insights should be valuable in developing new strategies to therapeutically target VEGF-C/VEGFR-3-induced lymphangiogenesis.
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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.