ArticleProceedings of the National Academy of Sciences of the United States of America2013
Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 120 citations in OpenAlex.
- Genetic Variants ofCancer research · 2019Trial
- Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib-Treated Cancer.CPT: pharmacometrics & systems pharmacology · 2017Trial
- A 3D lymphatics-on-a-chip reveals matrix stiffness dependent VEGFR-2 and VEGFR-3 contributions to lymphangiogenesis.Acta biomaterialia · 2026Article
- Structural Basis of Lymphangiogenic Receptor VEGFR-3 Activation Mediated by Distinctive Clustering of the Ligand-Receptor Complex.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Mechanisms of VEGFR2 activation by VEGF, neuropilin, and heparin.Science advances · 2026Article
- Computational design of synthetic receptors with programmable signalling activity for enhanced cancer T cell therapy.Nature biomedical engineering · 2026Article
- Direct Phasing of Protein Crystals with Hybrid Difference Map Algorithms.Molecules (Basel, Switzerland) · 2026Article
- Unraveling the impact of cancer-associated fibroblasts on lymphatic metastasis of head and neck squamous cell carcinoma.Cellular oncology (Dordrecht, Netherlands) · 2025Review
- Site-1 protease-mediated cholesterol metabolism is essential for lymphatic development in mice.JCI insight · 2025Article
- The Cerebral Lymphatic System: Function, Controversies, and Therapeutic Approaches for Central Nervous System Diseases.Cellular and molecular neurobiology · 2025Review
- Obesity Alters the Vascular Morphology and VEGF-A Signaling in Adipose Tissue.FASEB bioAdvances · 2025Article
- Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives.Signal transduction and targeted therapy · 2025Review
- Antiangiogenic Potential of Beneficial Sterols from Parotoid Gland Secretion of Indian Common Toads (ACS omega · 2025Article
- Lymphatic transport in anti-tumor immunity and metastasis.The Journal of experimental medicine · 2025Review
- Arterial-Lymphatic-Like Endothelial Cells Appear in Hereditary Hemorrhagic Telangiectasia 2 and Contribute to Vascular Leakage and Arteriovenous Malformations.Circulation · 2025Article
- Regulation of VEGFR3 signaling in lymphatic endothelial cells.Frontiers in cell and developmental biology · 2025Review
- Molecular Characterization and Interaction between Human VEGF-D and VEGFR-3.Journal of microbiology and biotechnology · 2024Article
- Analysis of crystallographic phase retrieval using iterative projection algorithms.Acta crystallographica. Section D, Structural biology · 2024Article
- Microvascular destabilization and intricated network of the cytokines in diabetic retinopathy: from the perspective of cellular and molecular components.Cell & bioscience · 2024Review
- Potential inhibitors of VEGFR1, VEGFR2, and VEGFR3 developed through Deep Learning for the treatment of Cervical Cancer.Scientific reports · 2024Article
6 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key drivers of blood and lymph vessel formation in development, but also in several pathological processes. VEGF-C signaling through VEGFR-3 promotes lymphangiogenesis, which is a clinically relevant target for treating lymphatic insufficiency and for blocking tumor angiogenesis and metastasis. The extracellular domain of VEGFRs consists of seven Ig homology domains; domains 1-3 (D1-3) are responsible for ligand binding, and the membrane-proximal domains 4-7 (D4-7) are involved in structural rearrangements essential for receptor dimerization and activation. Here we analyzed the crystal structures of VEGF-C in complex with VEGFR-3 domains D1-2 and of the VEGFR-3 D4-5 homodimer. The structures revealed a conserved ligand-binding interface in D2 and a unique mechanism for VEGFR dimerization and activation, with homotypic interactions in D5. Mutation of the conserved residues mediating the D5 interaction (Thr446 and Lys516) and the D7 interaction (Arg737) compromised VEGF-C induced VEGFR-3 activation. A thermodynamic analysis of VEGFR-3 deletion mutants showed that D3, D4-5, and D6-7 all contribute to ligand binding. A structural model of the VEGF-C/VEGFR-3 D1-7 complex derived from small-angle X-ray scattering data is consistent with the homotypic interactions in D5 and D7. Taken together, our data show that ligand-dependent homotypic interactions in D5 and D7 are essential for VEGFR activation, opening promising possibilities for the design of VEGFR-specific drugs.
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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.