ArticleThe FEBS journal2013
Endorepellin laminin-like globular 1/2 domains bind Ig3-5 of vascular endothelial growth factor (VEGF) receptor 2 and block pro-angiogenic signaling by VEGFA in endothelial cells.
Article in The FEBS journal, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 49 citations in OpenAlex.
- Structure and Function of the Extracellular Matrix in Normal and Pathological Conditions: Looking at the Bicuspid Aortic Valve.International journal of molecular sciences · 2025Review
- Proteoglycans and glycosaminoglycans: critical regulators in angiogenesis, vasculogenesis, and vascularized tissue engineering.Angiogenesis · 2025Review
- Recombinant Human Perlecan DV and Its LG3 Subdomain Are Neuroprotective and Acutely Functionally Restorative in Severe Experimental Ischemic Stroke.Translational stroke research · 2023Article
- Extracellular matrix guidance of autophagy: a mechanism regulating cancer growth.Open biology · 2022Review
- Impact of perlecan, a core component of basement membrane, on regeneration of cartilaginous tissues.Acta biomaterialia · 2021Review
- A functional outside-in signaling network of proteoglycans and matrix molecules regulating autophagy.Matrix biology : journal of the International Society for Matrix Biology · 2021Article
- Angiostatic cues from the matrix: Endothelial cell autophagy meets hyaluronan biology.The Journal of biological chemistry · 2020Review
- Review
- Endorepellin evokes an angiostatic stress signaling cascade in endothelial cells.The Journal of biological chemistry · 2020Article
- Expression and Circulating Levels of Perlecan in Breast Cancer - Implications for Oestrogen Dependent Stromal Remodeling.Journal of mammary gland biology and neoplasia · 2020Article
- Cancer Metastasis: The Role of the Extracellular Matrix and the Heparan Sulfate Proteoglycan Perlecan.Frontiers in oncology · 2019Review
- Endorepellin remodels the endothelial transcriptome toward a pro-autophagic and pro-mitophagic gene signature.The Journal of biological chemistry · 2018Article
- Collateral Damage Intended-Cancer-Associated Fibroblasts and Vasculature Are Potential Targets in Cancer Therapy.International journal of molecular sciences · 2017Review
- Decorin-inducible Peg3 Evokes Beclin 1-mediated Autophagy and Thrombospondin 1-mediated Angiostasis.The Journal of biological chemistry · 2017Article
- A current view of perlecan in physiology and pathology: A mosaic of functions.Matrix biology : journal of the International Society for Matrix Biology · 2017Review
- Endorepellin-evoked Autophagy Contributes to Angiostasis.The Journal of biological chemistry · 2016Article
- Molecular Functions of Glycoconjugates in Autophagy.Journal of molecular biology · 2016Review
- Endostatin and endorepellin: A common route of action for similar angiostatic cancer avengers.Advanced drug delivery reviews · 2016Review
- MULTIMERIN2 binds VEGF-A primarily via the carbohydrate chains exerting an angiostatic function and impairing tumor growth.Oncotarget · 2016Article
- Matricryptins Network with Matricellular Receptors at the Surface of Endothelial and Tumor Cells.Frontiers in pharmacology · 2016Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Endorepellin, a processed fragment of perlecan protein core, possesses anti-angiogenic activity by antagonizing endothelial cells. Endorepellin contains three laminin G-like (LG) domains and binds simultaneously to vascular endothelial growth factor receptor 2 (VEGFR2) and α2β1 integrin, resulting in dual receptor antagonism. Treatment of endothelial cells with endorepellin inhibits transcription of VEGFA, the natural ligand for VEGFR2, attenuating the pro-survival and migratory activities of VEGFA/VEGFR2 signaling cascade. Here, we investigated the specific binding site of endorepellin within the ectodomain of VEGFR2. Full-length endorepellin was not capable of displacing VEGFA binding from VEGFR2 and LG3 domain alone did not bind VEGFR2. This suggested different binding mechanisms of the extracellular Ig domains of VEGFR2. Therefore, we hypothesized that endorepellin would bind through its proximal LG1/2 domains to VEGFR2 in a different region than VEGFA. Indeed, we found that LG1/2 did not bind Ig1-3, but did bind with high affinity to Ig3-5, distal to the known VEGFA binding site, i.e. Ig2-3. These results support a role for endorepellin as an allosteric inhibitor of VEGFR2. Moreover, we found that LG1/2 blocked the rapid VEGFA activation of VEGFR2 at Tyr1175 in endothelial cells. In contrast, LG1/2 did not result in actin cytoskeletal disassembly in endothelial cells whereas LG3 alone did induce cytoskeletal collapse. However, LG1/2 did inhibit VEGFA-dependent endothelial migration through fibrillar collagen I. These studies provide a mechanistic understanding of how the different LG domains of endorepellin signal in endothelial cells while serving as a template for protein design of receptor tyrosine kinase antagonists.
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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.